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The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy

Key Points

  • p27 (also known as KIP1, and encoded by CDKN1B) is regulated by multiple signal transduction pathways in normal and malignant cells.

  • CDKN1B transcription can be regulated by the FoxO family and genetic defects that reduce CDKN1B transcription can predispose to multiple endocrine neoplasia (MEN)-like phenotypes.

  • CDKN1B 5′UTR mediates its cell cycle-dependent translation and several proteins can bind the CDKN1B IRES to modulate its translation.

  • micro-RNA-mediated inhibition of p27 translation emerges as a novel mechanism that can reduce p27 in some human cancers.

  • p27 proteolysis is initiated by several different mechanisms.

  • Tyrosine (Tyr) phosphorylation of p27 by Abl and Src family kinases reduces p27–CDK2 inhibition and transforms p27 from inhibitor to substrate of cyclin–CDK2 complexes.

  • p27 phosphorylation at Thr157 and Thr198 by members of the AGC kinase family promotes assembly of p27–cyclin D–CDK4/6, but catalytic activation requires tyrosine phosphorylation.

  • Cytoplasmic mislocalization of p27 is activated by AGC family kinases and contributes to RHOA inhibition and increased cell motility in cancers.

  • p27 levels are reduced in the most common and lethal human epithelial cancers and this is associated with poor patient outcome.

  • Restoration of p27 levels and/or nuclear localization may predict response to molecular therapies that target EGFR and IGFR families, MAP2K (also known as MEK), BCR-ABL and SRC.

Abstract

The cyclin-dependent kinase (Cdk) inhibitor p27 (also known as KIP1) regulates cell proliferation, cell motility and apoptosis. Interestingly, the protein can exert both positive and negative functions on these processes. Diverse post-translational modifications determine the physiological role of p27. Phosphorylation regulates p27 binding to and inhibition of cyclin–Cdk complexes, its localization and its ubiquitin-mediated proteolysis. In cancers, p27 is inactivated through impaired synthesis, accelerated degradation and by mislocalization. Moreover, studies in several tumour types indicate that p27 expression levels have both prognostic and therapeutic implications.

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Figure 1: Schematic model of p27 levels and regulation during G0/G1 to S phase.
Figure 2: Modelling effects of tyrosine phosphorylation on p27 on p27–CDK2.
Figure 3: Model of signalling pathways that regulate p27.
Figure 4: p27 expression levels and cancer.

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References

  1. Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501–1512 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Hengst, L. & Reed, S. I. Inhibitors of the Cip/Kip family. Curr. Top. Microbiol. Immunol. 227, 25–41 (1998)

    CAS  PubMed  Google Scholar 

  3. Nigg, E. A. Targets of cyclin-dependent protein kinases. Curr. Opin. Cell Biol. 199, 187–193 (1993).

    Article  Google Scholar 

  4. James, M., Ray, A., Leznova, D. & Blain, S. W. Differential modification of p27Kip1 controls its cyclin D–cdk4 inhibitory activity. Mol. Cell Biol. (2007). Showed that p27 in active cyclin D1–CDK4 complexes is phosphorylated on tyrosine whereas p27 in catalytically inactive cyclin D1–CDK4 is not.

  5. Grimmler, M. et al. Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases. Cell 128, 269–280 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Hengst, L. & Reed, S. I. Translational control of p27Kip1 accumulation during the cell cycle. Science 271, 1861–1864 (1996). This paper demonstrated that CDKN1B transcript levels vary little, but translation is maximal in quiescence and falls during G1 progression.

    Article  CAS  PubMed  Google Scholar 

  7. Liang, J. & Slingerland, J. M. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2, 339–345 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Besson, A., Assoian, R. K. & Roberts, J. M. Regulation of the cytoskeleton: an oncogenic function for CDK inhibitors? Nature Rev. Cancer 4, 948–955 (2004). An important review of primary work by these authors and others showing that cytoplasmic p27 has effects on cell motility that are, at least in part, independent of its Cdk regulatory functions.

    Article  CAS  Google Scholar 

  9. Slingerland, J. & Pagano, M. Regulation of the cdk inhibitor p27 and its deregulation in cancer. J. Cell Physiol. 183, 10–17 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Medema, R. H., Kops, G. J., Bos, J. L. & Burgering, B. M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782–787 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Dijkers, P. F. et al. Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27KIP1. Mol. Cell. Biol. 20, 9138–9148 (2000). References 10 and 11 were the first to show that p27 transcription is opposed by Akt action on forkhead transcription factors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Trotman, L. C. et al. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441, 523–527 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang, H. L., Zhao, R. Y., Yang, H. Y. & Lee, M. H. Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity. Oncogene 24, 1924–1935 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Wang, X. H. et al. Increased hepatic forkhead box M1B (FoxM1B) levels in old-aged mice stimulated liver regeneration through diminished p27(KiP1) protein levels and increased Cdc25B expression. J. Biol. Chem. 277, 44310–44316 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Karnik, S. K. et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27(Kip1) and p18(INK4c). Proc. Natl Acad. Sci. USA 102, 14659–14664 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fontaniere, S., Casse, H., Bertolino, P. & Zhang, C. X. Analysis of p27Kip1 expression in insulinomas developed in pancreatic β-cell specific Men1 mutant mice. Familial Cancer 5, 49–54 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Pellegata, N. S. et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc. Natl Acad. Sci. USA 103, 15558–15563 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Georgitsi, M. et al. Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers. Br. J. Cancer 96, 352–356 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yang, W. et al. Repression of transcription of the p27Kip1 cyclin-dependent kinase inhibitor gene by c-Myc. Oncogene 20, 1688–1702 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. O'Hagan, R. C. et al. Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression. Genes Dev. 14, 2185–2191 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Keller, U. B. et al. Myc targets Cks1 to provoke the suppression of p27Kip1, proliferation and lymphomagenesis. EMBO J. 26, 2562–2574 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang, C. G. et al. Activation of p27Kip1 expression by E2F1 — a negative feedback mechanism. J. Biol. Chem. 280, 12339–12343 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Inoue, T., Kamiyama, J. & Sakai, T. Sp1 and NF-Y synergistically mediate the effect of vitamin D-3 in the p27Kip1 gene promoter that lacks vitamin D response elements. J. Biol. Chem. 274, 32309–32317 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Murata, K. et al. Hes1 directly controls cell proliferation through the transcriptional repression of p27Kip1. Mol. Cell. Biol. 25, 4262–4271 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Huang, Y. C., Chen, J. Y. & Hung., W. C. Vitamin D-3 receptor/Sp1 complex is required for the induction of p27Kip1 expression by vitamin D-3. Oncogene 23, 4856–4861 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Agrawal, D. et al. Repression of p27kip1 synthesis by platelet-derived growth factor in BALB/c 3T3 cells. Mol. Cell Biol. 16, 4327–4336 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Millard, S. S. et al. Enhanced ribosomal association of p27Kip1 mRNA is a mechanism contributing to accumulation during growth arrest. J. Biol. Chem. 272, 7093–7098 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Gopfert, U., Kullmann, M. & Hengst, L. Cell cycle-dependent translation of p27 involves a responsive element in its 5′-UTR that overlaps with a uORF. Hum. Mol. Genet. 12, 1767–1779 (2003).

    Article  PubMed  CAS  Google Scholar 

  29. Miskimins, W. K., Wang, G., Hawkinson, M. & Miskimins, R. Control of cyclin-dependent kinase inhibitor p27 expression by cap-independent translation. Mol. Cell. Biol. 21, 4960–4967 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kullmann, M., Gopfert, U., Siewe, B. & Hengst, L. ELAV/Hu proteins inhibit p27 translation via an IRES element in the p27 5′ UTR. Genes Dev. 16, 3087–3099 (2002). Showed ELAV /Hu proteins bind an IRES in the 5′ UTR to impair p27 translation. Overexpression of ELAV in cancers might reduce p27 translation and contribute to development or progression of certain cancers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yoon, A. et al. Impaired control of IRES-mediated translation in X-linked dyskeratosis congenita. Science 312, 902–906 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Cho, S. C., Kim, J. H., Back, S. H. & Jang, S. K. Polypyrimidine tract-binding protein enhances the internal ribosomal entry site-dependent translation of p27Kip1 mRNA and modulates transition from G1 to S phase. Mol. Cell. Biol. 25, 1283–1297 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Millard, S. S., Vidal, A., Markus, M. & Koff, A. A U-rich element in the 5′ untranslated region is necessary for the translation of p27 mRNA. Mol. Cell Biol. 20, 5947–5959 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Erkinheimo, T. L. et al. Cytoplasmic HuR expression correlates with poor outcome and with cyclooxygenase 2 expression in serous ovarian carcinoma. Cancer Res. 63, 7591–7594 (2003).

    CAS  PubMed  Google Scholar 

  35. Denkert, C. et al. Overexpression of the embryonic-lethal abnormal vision-like protein HuR in ovarian carcinoma is a prognostic factor and is associated with increased cyclooxygenase 2 expression. Cancer Res. 64, 189–195 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. de Silanes, I. L. et al. Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene 22, 7146–7154 (2003).

    Article  CAS  Google Scholar 

  37. Vidal, A., Millard, S. S., Miller, J. P. & Koff, A. Rho activity can alter the translation of p27 mRNA and is important for RasV12-induced transformation in a manner dependent on p27 status. J. Biol. Chem. 277, 16433–16440 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Gonzalez, T. et al. Inhibition of Cdk4 activity enhances translation of p27kip1 in quiescent Rb-negative cells. J. Biol. Chem. 278, 12688–12695 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. le Sage, C., Nagel, R. & Agami, R. Diverse ways to control p27Kip1 function: miRNAs come into play. Cell Cycle 6, 2742–2749 (2007). Important recent review of work by these authors and others showing that p27 translation is reduced by miRNA-221/222 and might contribute to p27 loss in human cancer.

    Article  CAS  PubMed  Google Scholar 

  40. Kedde, M. et al. RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell 131, 1273–1286 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Galardi, S. et al. miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J. Biol. Chem. 282, 23716–23724 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Volinia, S. et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl Acad. Sci. USA 103, 2257–2261 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Visone, R. et al. MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle. Endocr. Relat. Cancer 14, 791–798 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Calin, G. A. et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N. Engl. J. Med. 353, 1793–1801 (2005). References 42–44 and others within reference 38 demonstrate overexpression of miRNA-221/222 in human neoplasia.

    Article  CAS  PubMed  Google Scholar 

  45. Nakayama, K. I. & Nakayama, K. Ubiquitin ligases: cell-cycle control and cancer. Nature Rev. Cancer 6, 369–381 (2006). Important review of primary work by these authors and others that covers proteolytic mechanisms governing p27 degradation.

    Article  CAS  Google Scholar 

  46. Bloom, J. & Pagano, M. Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Semin. Cancer Biol. 13, 41–47 (2003). Important conceptual review of p27 proteolysis by the SCFSKP2 ubiquitin ligase pathway.

    Article  CAS  PubMed  Google Scholar 

  47. Sabile, A. et al. Regulation of p27 degradation and S-phase progression by Ro52 RING finger protein. Mol. Cell. Biol. 26, 5994–6004 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pavletich, N. P. Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J. Mol. Biol. 287, 821–828 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Chu, I. et al. p27 phosphorylation by Src regulates inhibition of cyclin E–Cdk2. Cell 128, 281–294 (2007). References 5 and 49 first showed that tyrosine phosphorylation of p27 has effects on Cdk binding and promotes SCFSKP2-mediated p27 proteolysis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Russo, A. A., Jeffrey, P. D., Patten, A. K., Massague, J. & Pavletich, N. P. Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature 382, 325–331 (1996). Solved the crystal structure of the N-terminal fragment of p27 bound to cyclin A–CDK2.

    Article  CAS  PubMed  Google Scholar 

  51. Malek et al. A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase. Nature 413, 323–327 (2001)

    Article  CAS  PubMed  Google Scholar 

  52. Bondar, T. et al. Cu14A and DDB1 associate with Skp2 to target p27Kip1 for proteolysis involving the COP9 signalosome. Mol. Cell. Biol. 26, 2531–2539 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tomoda, K., Kubota, Y. & Kato, J. Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature 398, 160–165 (1999). References 52 & 53 indicate that p27 proteolysis might be linked to COP9 signalosome function.

    Article  CAS  PubMed  Google Scholar 

  54. Boehm, M. et al. A growth factor-dependent nuclear kinase phosphorylates p27(Kip1) and regulates cell cycle progression. EMBO J. 21, 3390–3401 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Deng, X., Mercer, S. E., Shah, S., Ewton, D. Z. & Friedman, E. The cyclin-dependent kinase inhibitor p27Kip1 is stabilized in G0 by Mirk/dyrk1B kinase. J. Biol. Chem. 279, 22498–22504 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Rodier, G. et al. p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. EMBO J. 20, 6672–6682 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ishida, N. et al. Phosphorylation of p27Kip1 on serine 10 is required for its binding to CRM1 and nuclear export. J. Biol. Chem. 277, 14355–14358 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Connor, M. K. et al. CRM1/Ran-mediated nuclear export of p27Kip1 involves a nuclear export signal and links p27 export and proteolysis. Mol. Biol. Cell 14, 201–213 (2003). References 56–58 demonstrate that p27 is exported from the nucleus in a CRM1-dependent manner and show serine 10 phosphorylation promotes nuclear export.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Besson, A. et al. A pathway in quiescent cells that controls p27Kip1 stability, subcellular localization, and tumor suppression. Genes Dev. 20, 47–64 (2006). This paper showed that serine 10 phosphorylation regulates p27 stability in G0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Liang, J. et al. The energy sensing LKB-1–AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis. Nature Cell Biol. 9, 218–224 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Kossatz, U. et al. C-terminal phosphorylation controls the stability and function of p27kip1. EMBO J. 25, 5159–5170 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kotake, Y., Nakayama, K., Ishida, N. & Nakayama, K. I. Role of serine 10 phosphorylation in p27 stabilization revealed by analysis of p27 knock-in mice harboring a serine 10 mutation. J. Biol. Chem. 280, 1095–1102 (2005). This paper showed that serine 10 phosphorylation regulates p27 stability in G0.

    Article  CAS  PubMed  Google Scholar 

  63. Ishizawar, R. & Parsons, S. J. c-Src and cooperating partners in human cancer. Cancer Cell 6, 209–214 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Pegram, M. D., Pauletti, G. & Slamon, D. J. HER-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res. Treat. 52, 65–77 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Arteaga, C. L. & Baselga, J. Clinical trial design and end points for epidermal growth factor receptor-targeted therapies: implications for drug development and practice. Clin. Cancer Res. 9, 1579–1589 (2003).

    CAS  PubMed  Google Scholar 

  66. Spataro, V. J. et al. Decreased immunoreactivity for p27 protein in patients with early-stage breast carcinoma is correlated with HER-2/neu overexpression and with benefit from one course of perioperative chemotherapy in patients with negative lymph node status: results from International Breast Cancer Study Group Trial, V. Cancer 97, 1591–1600 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Newman, L. et al. Correlation of p27 protein expression with HER-2/neu expression in breast cancer. Mol. Carcinog. 30, 169–175 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Donovan, J. C., Milic, A. & Slingerland, J. M. Constitutive MEK/MAPK activation leads to p27Kip1 deregulation and antiestrogen resistance in human breast cancer cells. J. Biol. Chem. 276, 40888–40895 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Yang, H. Y., Zhou, B. P., Hung., M. C. & Lee, M. H. Oncogenic signals of HER-2/neu in regulating the stability of the cyclin-dependent kinase inhibitor p27. J. Biol. Chem. 275, 24735–24739 (2000). This paper demonstrated that p27 proteolysis is activated by overexpression of Her2.

    Article  CAS  PubMed  Google Scholar 

  70. Nahta, R., Takahashi, T., Ueno, N. T., Hung., M. C. & Esteva, F. J. P27kip1 down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res. 64, 3981–3986 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Busse, D. et al. Reversible G1 arrest induced by inhibition of the epidermal growth factor receptor tyrosine kinase requires up-regulation of p27KIP1 independent of MAPK activity. J. Biol. Chem. 275, 6987–6995 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Chu, I., Blackwell, K., Chen, S. & Slingerland, J. The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer. Cancer Res. 65, 18–25 (2005).

    CAS  PubMed  Google Scholar 

  73. Moller, M. B., Skjodt, K., Mortensen, L. S. & Pedersen, N. T. Clinical significance of cyclin-dependent kinase inhibitor p27Kip1 expression and proliferation in non-Hodgkin's lymphoma: independent prognostic value of p27Kip1. Br. J. Haematol. 105, 730–736 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Tsihlias, J., Kapusta, L. & Slingerland, J. The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu. Rev. Med. 50, 401–423 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Andreu, E. J. et al. BCR-ABL induces the expression of Skp2 through the PI3K pathway to promote p27Kip1 degradation and proliferation of chronic myelogenous leukemia cells. Cancer Res. 65, 3264–3272 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Donato, N. J. et al. BCR–ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 101, 690–698 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nature Rev. Cancer 2, 489–501 (2002).

    Article  CAS  Google Scholar 

  78. Tsutsui, S. et al. Inactivation of PTEN is associated with a low p27Kip1 protein expression in breast carcinoma. Cancer 104, 2048–2053 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Latres, E. et al. Role of the F-box protein Skp2 in lymphomagenesis. Proc. Natl Acad. Sci. USA 98, 2515–2520 (2001). First demonstration that SKP2 is overexpressed in human lymphoma and that SKP2 overexpression promotes lymphoma progression in a mouse model in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chiarle, R. et al. Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma. Blood 95, 619–626 (2000).

    CAS  PubMed  Google Scholar 

  81. Hershko, D. et al. Inverse relation between levels of p27Kip1 and of its ubiquitin ligase subunit Skp2 in colorectal carcinomas. Cancer 91, 1745–1751 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Shapira, M. et al. The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma. Cancer 103, 1336–1346 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Signoretti, S. et al. Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer. J. Clin. Invest. 110, 633–641 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Shintani, S. et al. Skp2 and Jab1 expression are associated with inverse expression of p27KIP1 and poor prognosis in oral squamous cell carcinomas. Oncology 65, 355–362 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Kudo, Y. et al. High expression of S-phase kinase-interacting protein 2, human F-box protein, correlates with poor prognosis in oral squamous cell carcinomas. Cancer Res. 61, 7044–7047 (2001).

    CAS  PubMed  Google Scholar 

  86. Gstaiger, M. et al. Skp2 is oncogenic and overexpressed in human cancers. Proc. Natl Acad. Sci. USA 98, 5043–5048 (2001). First demonstrated overexpression and oncogenicity of SKP2 in human epithelial cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Drobnjak, M. et al. Altered expression of p27 and Skp2 proteins in prostate cancer of African-American patients. Clin. Cancer Res. 9, 2613–2619 (2003).

    CAS  PubMed  Google Scholar 

  88. Yokoi, S. et al. A novel target gene, SKP2, within the 5p13 amplicon that is frequently detected in small cell lung cancers. Am. J. Pathol. 161, 207–216 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Masuda, T. A. et al. Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma: modulation of malignant phenotype by Skp2 overexpression, possibly via p27 proteolysis. Cancer Res. 62, 3819–3825 (2002).

    CAS  PubMed  Google Scholar 

  90. Nakayama, K. et al. Skp2-mediated degradation of p27 regulates progression into mitosis. Dev. Cell 6, 661–672 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Kossatz, U. et al. Skp2-dependent degradation of p27kip1 is essential for cell cycle progression. Genes Dev. 18, 2602–2607 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Catzavelos, C. et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nature Med. 3, 227–230 (1997).

    Article  CAS  PubMed  Google Scholar 

  93. Porter, P. L. et al. Expression of cell cycle regulators p27kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nature Med. 3, 222–225 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Tan, P. et al. The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a, b) invasive breast carcinomas. Cancer Res. 57, 1259–1263 (1997). References 92–94 were the first to demonstrate that p27 levels are frequently reduced in human breast cancer and that this is prognostic for poor patient outcome on multivariate analysis.

    CAS  PubMed  Google Scholar 

  95. Zeng, Y., Hirano, K., Hirano, M., Nishimura, J. & Kanaide, H. Minimal requirements for the nuclear localization of p27Kip1, a cyclin-dependent kinase inhibitor. Biochem. Biophys. Res. Commun. 274, 37–42 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. LaBaer, J. et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev. 11, 847–862 (1997).

    Article  CAS  PubMed  Google Scholar 

  97. Cheng, M. et al. The p21Cip1 and p27Kip1 CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J. 18, 1571–1583 (1999). References 96 and 97 provide biochemical and genetic evidence that p27 and p21 regulate the assembly of D-type cyclin–Cdk complexes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Liang, J. et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nature Med. 8, 1153–1160 (2002). This paper showed that Akt phosphorylated p27 to impair its nuclear import.

    Article  CAS  PubMed  Google Scholar 

  99. Shin, I., Rotty, J., Wu, F. Y. & Arteaga, C. L. Phosphorylation of p27Kip1 at Thr-157 interferes with its association with importin alpha during G1 and prevents nuclear re-entry. J. Biol. Chem. 280, 6055–6063 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Sekimoto, T., Fukumoto, M. & Yoneda, Y. 14-3-3 suppresses the nuclear localization of threonine 157-phosphorylated p27Kip1. EMBO J. 23, 1934–1942 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Fujita, N., Sato, S., Katayama, K. & Tsuruo, T. Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. J. Biol. Chem. 277, 28706–28713 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Fujita, N., Sato, S. & Tsuruo, T. Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization. J. Biol. Chem. 278, 49254–49260 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Kardinal, C. et al. Tyrosine phosphorylation modulates binding preference to cyclin-dependent kinases and subcellular localization of p27Kip1 in the acute promyelocytic leukemia cell line NB4. Blood 107, 1133–1140 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Soos, T. J. et al. Formation of p27–CDK complexes during the human mitotic cell cycle. Cell Growth Differ. 7, 135–146 (1996).

    CAS  PubMed  Google Scholar 

  105. Zhang, H., Hannon, G. & Beach, D. p21-containing cyclin kinases exist in both active and inactive states. Genes Dev. 8, 1750–1758 (1994).

    Article  CAS  PubMed  Google Scholar 

  106. Nagahara, H. et al. Transduction of full-length TAT fusion proteins into mammalian cells: TAT–p27Kip1 induces cell migration. Nature Med. 4, 1449–1452 (1998).

    Article  CAS  PubMed  Google Scholar 

  107. Cheng, M., Sexl, V., Sherr, C. J. & Roussel, M. F. Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1). Proc. Natl Acad. Sci. USA. 95, 1091–1096 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Liu, X. et al. Disruption of TGF-β growth inhibition by oncogenic ras is linked to p27Kip1 mislocalization. Oncogene 19, 5926–5935 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Viglietto, G. et al. Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27Kip1 by PKB/Akt-mediated phosphorylation in breast cancer. Nature Med. 8, 1136–1144 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Shin, I. et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27Kip1 at threonine 157 and modulation of its cellular localization. Nature Med. 8, 1145–1152 (2002). References 98, 109 and 110 were published together and all showed that cytoplasmic mislocalization of p27 in human breast cancer was associated with activation of Akt.

    Article  CAS  PubMed  Google Scholar 

  111. Viglietto, G. & Fusco, A. Understanding p27kip1 deregulation in cancer: down-regulation or mislocalization? Cell Cycle 1, 394–400 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Motti, M. L., De Marco, C., Califano, D., Fusco, A. & Viglietto, G. Akt-dependent T198 phosphorylation of cyclin-dependent kinase inhibitor p27kip1 in breast cancer. Cell Cycle 3, e89–e95 (2004).

    Article  Google Scholar 

  113. Psyrri, A. et al. Subcellular localization and protein levels of cyclin-dependent kinase inhibitor p27 independently predict for survival in epithelial ovarian cancer. Clin. Cancer Res. 11, 8384–8390 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Baldassarre, G. et al. p27Kip1-stathmin interaction influences sarcoma cell migration and invasion. Cancer Cell 7, 51–63 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. McAllister, S. S., Becker-Hapak, M., Pintucci, G., Pagano, M. & Dowdy, S. F. Novel p27kip1 C-terminal scatter domain mediates Rac-dependent cell migration independent of cell cycle arrest functions. Mol. Cell Biol. 23, 216–228 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wu, F. Y. et al. Reduction of cytosolic p27Kip1 inhibits cancer cell motility, survival, and tumorigenicity. Cancer Res. 66, 2162–2172 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. Denicourt, C., Saenz, C. C., Datnow, B., Cui, X. S. & Dowdy, S. F. Relocalized p27KiP1 tumor suppressor functions as a cytoplasmic metastatic oncogene in melanoma. Cancer Res. 67, 9238–9243 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Besson, A. et al. Discovery of an oncogenic activity in p27Kip1 that causes stem cell expansion and a multiple tumor phenotype. Genes Dev. 21, 1731–1746 (2007). Identified a novel pro-oncogenic action of p27 to promote expansion of cells with self-renewal capacity or tumour-initiating function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Jordan, R., Bradley, G. & Slingerland, J. M. Reduced levels of the cell-cycle inhibitor p27KIP1 in epithelial dysplasia and carcinoma of the oral cavity. Am. J. Pathol. 152, 1–6 (1998).

    Google Scholar 

  120. De Paola, F. et al. p27/kip1 expression in normal epithelium, benign and neoplastic breast lesions. J. Pathol. 196, 26–31 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Moriya, T. et al. Immunohistochemical analysis of Ki-67, p53, p21, and p27 in benign and malignant apocrine lesions of the breast: its correlation to histologic findings in 43 cases. Mod. Pathol. 13, 13–18 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Oh, Y. L. et al. Expression of p21Waf1, p27Kip1 and cyclin D1 proteins in breast ductal carcinoma in situ: Relation with clinicopathologic characteristics and with p53 expression and estrogen receptor status. Path. Int. 51, 94–99 (2001).

    Article  CAS  Google Scholar 

  123. Han, S. et al. Reduced expression of p27Kip1 protein is associated with poor clinical outcome of breast cancer patients treated with systemic chemotherapy and is linked to cell proliferation and differentiation. Breast Cancer Res. Treat. 55, 161–167 (1999).

    Article  CAS  PubMed  Google Scholar 

  124. Massarelli, E. et al. Loss of E-cadherin and p27 expression is associated with head and neck squamous tumorigenesis. Cancer 103, 952–959 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. Pruneri, G. et al. Clinical relevance of expression of the CIP/KIP cell-cycle inhibitors p21 and p27 in laryngeal cancer. J. Clin. Oncol. 17, 3150–3159 (1999).

    Article  CAS  PubMed  Google Scholar 

  126. Vis, A. N. et al. Prognostic value of cell cycle proteins p27kip1 and MIB-1, and the cell adhesion protein CD44s in surgically treated patients with prostate cancer. J. Urol. 164, 2156–2161 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. Cordon-Cardo, C. et al. Distinct altered patterns of p27KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma. J. Natl Cancer Inst. 90, 1284–1291 (1998).

    Article  CAS  PubMed  Google Scholar 

  128. Tsihlias, J. et al. Loss of cyclin-dependent kinase inhibitor p27Kip1 is a novel prognostic factor in localized human prostate adenocarcinoma. Cancer Res. 58, 542–548 (1998).

    CAS  PubMed  Google Scholar 

  129. Sui, L. et al. Implication of malignancy and prognosis of p27Kip1, Cyclin E, and Cdk2 expression in epithelial ovarian tumors. Gynecol. Oncol. 83, 56–63 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Korkolopoulou, P. et al. The combined evaluation of p27Kip1 and Ki-67 expression provides independent information on overall survival of ovarian carcinoma patients. Gynecol. Oncol. 85, 404–414 (2002).

    Article  PubMed  Google Scholar 

  131. Yatabe, Y. et al. p27Kip1 in human lung cancers: differential changes in small cell and non-small cell carcinomas. Cancer Res. 58, 1042–1047 (1998).

    CAS  PubMed  Google Scholar 

  132. Ishihara, S. et al. The cyclin-dependent kinase inhibitor p27 as a prognostic factor in advanced non-small cell lung cancer: its immunohistochemical evaluation using biopsy specimens. Lung Cancer 26, 187–194 (1999).

    Article  CAS  PubMed  Google Scholar 

  133. Hommura, F. et al. Prognostic significance of p27KIP1 protein and ki-67 growth fraction in non-small cell lung cancers. Clin. Cancer Res. 6, 4073–4081 (2000).

    CAS  PubMed  Google Scholar 

  134. Tsukamoto, S. et al. Reduced expression of cell-cycle regulator p27Kip1 correlates with a shortened survival in non-small cell lung cancer. Lung Cancer 34, 83–90 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Hayashi, H. et al. High cyclin E and low p27/Kip1 expressions are potentially poor prognostic factors in lung adenocarcinoma patients. Lung Cancer 34, 59–65 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Hirabayashi, H. et al. Prognostic significance of p27KIP1 expression in resected non-small cell lung cancers: analysis in combination with expressions of p16INK4A, pRB, and p53. J. Surg. Oncol. 81, 177–184 (2002).

    Article  PubMed  Google Scholar 

  137. Takahashi, S. et al. Relationship between postoperative recurrence and expression of cyclin E, p27, and Ki-67 in non-small cell lung cancer without lymph node metastases. Int. J. Clin. Oncol. 7, 349–355 (2002).

    Article  CAS  PubMed  Google Scholar 

  138. Catzavelos, C. et al. Reduced expression of the cell cycle inhibitor p27Kip1 in non-small cell lung carcinoma: a potential prognostic factor independent of ras. Cancer Res. 59, 684–688 (1999).

    CAS  PubMed  Google Scholar 

  139. Esposito, V. et al. Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Res. 57, 3381–3385 (1997).

    CAS  PubMed  Google Scholar 

  140. Hirsch, F. R. et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: Correlation between gene copy number and protein expression and impact on prognosis. J. Clin. Oncol. 21, 3798–3807 (2003).

    Article  CAS  PubMed  Google Scholar 

  141. Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. Amann, J. et al. Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Res. 65, 226–235 (2005).

    CAS  PubMed  Google Scholar 

  143. Anayama, T., Furihata, M., Ishikawa, T., Ohtsuki, Y. & Ogoshi, S. Positive correlation between p27Kip1 expression and progression of human esophageal squamous cell carcinoma. Int. J. Cancer 79, 439–443 (1998).

    Article  CAS  PubMed  Google Scholar 

  144. Fan, G. K. et al. Expression of protein p27 is associated with progression and prognosis in laryngeal cancer. Laryngoscope 109, 815–820 (1999).

    Article  CAS  PubMed  Google Scholar 

  145. Itami, A., Shimada, Y., Watanabe, G. & Imamura, M. Prognostic value of p27Kip1 and CyclinD1 expression in esophageal cancer. Oncology 57, 311–317 (1999).

    Article  CAS  PubMed  Google Scholar 

  146. Mineta, H. et al. Low p27 expression correlates with poor prognosis for patients with oral tongue squamous cell carcinoma. Cancer 85, 1011–1017 (1999).

    Article  CAS  PubMed  Google Scholar 

  147. Fujieda, S. et al. Expression of p27 is associated with Bax expression and spontaneous apoptosis in oral and oropharyngeal carcinoma. Int. J. Cancer 84, 315–320 (1999).

    Article  CAS  PubMed  Google Scholar 

  148. Venkatesan, T. K. et al. Prognostic significance of p27 expression in carcinoma of the oral cavity and oropharynx. Laryngoscope 109, 1329–1333 (1999).

    Article  CAS  PubMed  Google Scholar 

  149. Shamma, A. et al. Loss of p27KIP1 expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. Oncology 58, 152–158 (2000).

    Article  CAS  PubMed  Google Scholar 

  150. Kagawa, Y., Yoshida, K., Hirai, T. & Toge, T. Significance of the expression of p27Kip1 in esophageal squamous cell carcinomas. Dis. Esophagus. 13, 179–184 (2000).

    Article  CAS  PubMed  Google Scholar 

  151. Tamura, N. et al. Cyclin-dependent kinase inhibitor p27 is related to cell proliferation and prognosis in laryngeal squamous cell carcinomas. J. Laryngol. Otol. 115, 400–406 (2001).

    Article  CAS  PubMed  Google Scholar 

  152. Kuo, M. Y. et al. Prognostic role of p27Kip1 expression in oral squamous cell carcinoma in Taiwan. Oral Oncol. 38, 172–178 (2002).

    Article  CAS  PubMed  Google Scholar 

  153. Korkmaz, H. et al. Prognostic significance of G1 cell-cycle inhibitors in early laryngeal cancer. Am. J. Otolaryngol. 26, 77–82 (2005).

    Article  CAS  PubMed  Google Scholar 

  154. Langer, R. et al. Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study. J. Clin. Pathol. 59, 631–634 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Loda, M. et al. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nature Med. 3, 231–234 (1997). Among the first studies to show loss of p27 protein expression is prognostic in human cancer. Showed that lysates from colon cancers with low p27 levels exhibit proteolytic activity toward recombinant p27 in vitro.

    Article  CAS  PubMed  Google Scholar 

  156. Belluco, C. et al. Absence of the cell cycle inhibitor p27Kip1 protein predicts poor outcome in patients with stage I–III colorectal cancer. Ann. Surg. Oncol. 6, 19–25 (1999).

    Article  CAS  PubMed  Google Scholar 

  157. Palmqvist, R., Stenling, R., Oberg, A. & Landberg, G. Prognostic significance of p27Kip1 expression in colorectal cancer: a clinico-pathological characterization. J. Pathol. 188, 18–23 (1999).

    Article  CAS  PubMed  Google Scholar 

  158. Tenjo, T. et al. Prognostic significance of p27kip1 protein expression and spontaneous apoptosis in patients with colorectal adenocarcinomas. Oncology 58, 45–51 (2000).

    Article  CAS  PubMed  Google Scholar 

  159. Rossi, H. A. et al. The prognostic value of invariant chain (Ii) and her-2/neu expression in curatively resected colorectal cancer. Cancer J. 8, 268–275 (2002).

    Article  PubMed  Google Scholar 

  160. Noguchi, T. et al. Prognostic significance of p27/kip1 and apoptosis in patients with colorectal carcinoma. Oncol. Rep. 10, 827–831 (2003).

    CAS  PubMed  Google Scholar 

  161. Galizia, G. et al. Determination of molecular marker expression can predict clinical outcome in colon carcinomas. Clin. Cancer Res. 10, 3490–3499 (2004).

    Article  CAS  PubMed  Google Scholar 

  162. Manne, U. et al. Prognostic significance of p27(kip-1) expression in colorectal adenocarcinomas is associated with tumor stage. Clin. Cancer Res. 10, 1743–1752 (2004).

    Article  CAS  PubMed  Google Scholar 

  163. Rosati, G., Chiacchio, R., Reggiardo, G., De Sanctis, D. & Manzione, L. Thymidylate synthase expression, p53, bcl-2, Ki-67 and p27 in colorectal cancer: relationships with tumor recurrence and survival. Tumour Biol. 25, 258–263 (2004).

    Article  CAS  PubMed  Google Scholar 

  164. Wu, J. T. et al. Prognostic significance of DCC and p27Kip1 in colorectal cancer. Appl. Immunohistochem. Mol. Morphol. 13, 45–54 (2005).

    Article  CAS  PubMed  Google Scholar 

  165. Watson, N. F. et al. Cytoplasmic expression of p27kip1 is associated with a favourable prognosis in colorectal cancer patients. World J. Gastroenterol. 12, 6299–6304 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Sarli, L. et al. Loss of p27 expression and microsatellite instability in sporadic colorectal cancer. Surg. Oncol. 15, 97–106 (2006).

    Article  PubMed  Google Scholar 

  167. Ciaparrone, M. et al. Localization and expression of p27KIP1 in multistage colorectal carcinogenesis. Cancer Res. 58, 114–122 (1998).

    CAS  PubMed  Google Scholar 

  168. Cheng, J. D., Werness, B. A., Babb, J. S. & Meropol, N. J. Paradoxical correlations of cyclin-dependent kinase inhibitors p21waf1/cip1 and p27kip1 in metastatic colorectal carcinoma. Clin. Cancer Res. 5, 1057–1062 (1999).

    CAS  PubMed  Google Scholar 

  169. Galizia, G. et al. Prognostic value of p27, p53, and vascular endothelial growth factor in Dukes A and B colon cancer patients undergoing potentially curative surgery. Dis. Colon Rectum 47, 1904–1914 (2004).

    Article  PubMed  Google Scholar 

  170. Yang, R. M. et al. Low p27 expression predicts poor disease-free survival in patients with prostate cancer. J. Urol. 159, 941–945 (1998).

    Article  CAS  PubMed  Google Scholar 

  171. Cote, R. J. et al. Association of p27Kip1 levels with recurrence and survival in patients with stage C prostate carcinoma. J. Natl Cancer Inst. 90, 916–920 (1998).

    Article  CAS  PubMed  Google Scholar 

  172. Freedland, S. J. et al. Preoperative p27 status is an independent predictor of prostate specific antigen failure following radical prostatectomy. J. Urol. 169, 1325–1330 (2003).

    Article  CAS  PubMed  Google Scholar 

  173. Li, R. et al. Biological correlates of p27 compartmental expression in prostate cancer. J. Urol. 175, 528–532 (2006).

    Article  CAS  PubMed  Google Scholar 

  174. Kuczyk, M. A. et al. Predictive value of altered p27Kip1 and p21WAF/Cip1 protein expression for the clinical prognosis of patients with localized prostate cancer. Oncol. Rep. 8, 1401–1407 (2001).

    CAS  PubMed  Google Scholar 

  175. Cheville, J. C. et al. Expression of p27kip1 in prostatic adenocarcinoma. Mod. Pathol. 11, 324–328 (1998).

    CAS  PubMed  Google Scholar 

  176. Thomas, G. V. et al. Preoperative prostate needle biopsy p27 correlates with subsequent radical prostatectomy p27, Gleason grade and pathological stage. J. Urol. 164, 1987–1991 (2000).

    Article  CAS  PubMed  Google Scholar 

  177. Freedland, S. J. et al. Predicting biochemical recurrence after radical prostatectomy for patients with organ-confined disease using p27 expression. Urology 61, 1187–1192 (2003).

    Article  PubMed  Google Scholar 

  178. Newcomb, E. W. et al. Expression of the cell cycle inhibitor p27KIP1 is a new prognostic marker associated with survival in epithelial ovarian tumors. Am. J. Pathol. 154, 119–125 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Baekelandt, M., Holm, R., Trope, C. G., Nesland, J. M. & Kristensen, G. B. Lack of independent prognostic significance of p21 and p27 expression in advanced ovarian cancer: an immunohistochemical study. Clin. Cancer Res. 5, 2848–2853 (1999).

    CAS  PubMed  Google Scholar 

  180. Masciullo, V. et al. p27Kip1 expression is associated with clinical outcome in advanced epithelial ovarian cancer: multivariate analysis. Clin. Cancer Res. 6, 4816–4822 (2000).

    CAS  PubMed  Google Scholar 

  181. Schmider-Ross, A. et al. Cyclin-dependant kinase inhibitors CIP1 (p21) and KIP1 (p27) in ovarian cancer. J. Cancer Res. Clin. Oncol. 132, 163–170 (2006).

    Article  CAS  PubMed  Google Scholar 

  182. Barnes, A. et al. Expression of p27kip I in breast cancer and its prognostic significance. J. Pathology 201, 451–459 (2003).

    Article  CAS  Google Scholar 

  183. Gillett, C. E., Smith, P., Peters, G., Lu, X. & Barnes, D. M. Cyclin-dependent kinase inhibitor p27Kip1 expression and interaction with other cell cycle-associated proteins in mammary carcinoma. J. Pathol. 187, 200–206 (1999).

    Article  CAS  PubMed  Google Scholar 

  184. Barbareschi, M. et al. p27kip1 expression in breast carcinomas: an immunohistochemical study on 512 patients with long-term follow-up. Int. J. Cancer 89, 236–241 (2000).

    Article  CAS  PubMed  Google Scholar 

  185. Leivonen, M., Nordling, S., Lundin, J., von Boguslawski, K. & Haglund, C. p27 expression correlates with short-term, but not with long-term prognosis in breast cancer. Breast Cancer Res. Treat. 67, 15–22 (2001).

    Article  CAS  PubMed  Google Scholar 

  186. Han, S. et al. Prognostic implication of cyclin E expression and its relationship with cyclin D1 and p27Kip1 expression on tissue microarrays of node negative breast cancer. J. Surg. Oncol. 83, 241–247 (2003).

    Article  PubMed  Google Scholar 

  187. Porter, P. L. et al. p27Kip1 and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy. J. Natl Cancer Inst. 98, 1723–1731 (2006). An important paper confirming the prognostic potential of p27 and shows that p27 loss is most prognostic in ER-positive human breast cancers in retrospective analysis of samples from a prospective randomized clinical trial.

    Article  CAS  PubMed  Google Scholar 

  188. Wu, J. et al. Prognostic role of p27Kip1 and apoptosis in human breast cancer. Br. J. Cancer 79, 1572–1578 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Tsuchiya, A., Zhang, G. J. & Kanno, M. Prognostic impact of cyclin-dependent kinase inhibitor p27kip1 in node-positive breast cancer. J. Surg. Oncol. 70, 230–234 (1999).

    Article  CAS  PubMed  Google Scholar 

  190. Chappuis, P. O. et al. Germline BRCA1/2 mutations and p27Kip1 protein levels independently predict outcome after breast cancer. J. Clin. Oncol. 18, 4045–4052 (2000).

    Article  CAS  PubMed  Google Scholar 

  191. Nohara, T., Ryo, T., Iwamoto, S., Gon, G. & Tanigawa, N. Expression of cell-cycle regulator p27 is correlated to the prognosis and ER expression in breast carcinoma patients. Oncology 60, 94–100 (2001).

    Article  CAS  PubMed  Google Scholar 

  192. Pohl, G. et al. High p27Kip1 expression predicts superior relapse-free and overall survival for premenopausal women with early-stage breast cancer receiving adjuvant treatment with tamoxifen plus goserelin. J. Clin. Oncol. 21, 3594–3600 (2003). The first study showing the predictive potential of p27 in a prospective trial. This important study showed that reduced p27 levels correlate with poor outcome in multivariate analysis and reduced response to endocrine therapy in pre-menopausal women with breast cancer in a retrospective analysis of p27 in samples collected in a prospective clinical trial.

    Article  CAS  PubMed  Google Scholar 

  193. Foulkes, W. D. et al. The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res. 64, 830–835 (2004).

    Article  CAS  PubMed  Google Scholar 

  194. Reed, W., Florems, V. A., Holm, R., Hannisdal, E. & Nesland, J. M. Elevated levels of p27, p21 and cyclin D1 correlate with positive oestrogen and progesterone receptor status in node-negative breast carcinoma patients. Virchows Arch. 435, 116–124 (1999).

    Article  CAS  PubMed  Google Scholar 

  195. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    Article  CAS  PubMed  Google Scholar 

  196. Osborne, C. K. Steroid hormone receptors in breast cancer management. Breast Cancer Res. Treat. 51, 227–238 (1998).

    Article  CAS  PubMed  Google Scholar 

  197. Oka, K., Suzuki, Y. & Nakano, T. Expression of p27 and p53 in cervical squamous cell carcinoma patients treated with radiotherapy alone: radiotherapeutic effect and prognosis. Cancer 88, 2766–2773 (2000).

    Article  CAS  PubMed  Google Scholar 

  198. Cariou, S. et al. Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells. Proc. Natl Acad. Sci. USA 97, 9042–9046 (2000). This paper demonstrated that p27 and p21 are required for growth arrest by tamoxifen and other antioestrogens in breast cancer cells in culture.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Lane, H. A. et al. ErbB2 potentiates breast tumor proliferation through modulation of p27Kip1–CDK2 complex formation: receptor overexpression does not determine growth dependency. Mol. Cell Biol. 20, 3210–3223 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Hayes, D. F. Prognostic and predictive factors for breast cancer: translating technology to oncology. J. Clin. Oncol. 23, 1596–1597 (2005).

    Article  PubMed  Google Scholar 

  201. Van't Veer, L. J., Paik, S. & Hayes, D. F. Gene expression profiling of breast cancer: a new tumor marker. J. Clin. Oncol. 23, 1631–1635 (2005).

    Article  CAS  PubMed  Google Scholar 

  202. Oshita, F. et al. Increased expression levels of cyclin-dependent kinase inhibitor p27 correlate with good responses to platinum-based chemotherapy in non-small cell lung cancer. Oncol. Rep. 7, 491–495 (2000).

    CAS  PubMed  Google Scholar 

  203. Kobayashi, M., Shiraishi, T., Tonouchi, H., Miki, C. & Kusunoki, M. 5-FU improves p27-related poor prognosis in patients with Astler-Coller B2-C colorectal carcinoma. Oncol. Rep. 9, 29–33 (2002).

    CAS  PubMed  Google Scholar 

  204. Prall, F., Ostwald, C., Nizze, H. & Barten, M. Expression profiling of colorectal carcinomas using tissue microarrays: cell cycle regulatory proteins p21, p27, and p53 as immunohistochemical prognostic markers in univariate and multivariate analysis. Appl. Immunohistochem. Mol. Morphol. 12, 111–121 (2004).

    Article  PubMed  Google Scholar 

  205. Singh, S. P. et al. Loss or altered subcellular localization of p27 in Barrett's associated adenocarcinoma. Cancer Res. 58, 1730–1735 (1998).

    CAS  PubMed  Google Scholar 

  206. Zeng, W. Q. et al. Relationships between levels of Skp2 and p27 in breast carcinomas and possible role of Skp2 as targeted therapy. Steroids 70, 770–774 (2005).

    Article  CAS  Google Scholar 

  207. Chang, J. et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy J. Natl Cancer Inst. (in the press).

  208. Hattori, T. et al. Pirh2 promotes ubiquitin-dependent degradation of the cyclin-dependent kinase inhibitor p27Kip1. Cancer Res. 67, 10789–10795 (2007).

    Article  CAS  PubMed  Google Scholar 

  209. Hauck, L. et al. Protein kinase CK2 links extracellular growth factor signaling with the control of p27Kip1 stability in the heart. Nature Med. 14, 315–324 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by National Cancer Institute grant 1R01CA105118-01 to J.M.S. and by Austrian Science Fund (FWF, Projects P-18873 and Special Research Program “Cell Proliferation and Cell Death in Tumours” Grant SFB021) to L.H. J.M.S. is supported by the Braman Family Breast Cancer Institute of the University of Miami Sylvester Comprehensive Cancer Center. The authors apologize for omissions in citation and coverage. Strict space and citation limits preculde inclusion of many important past and recent works. We thank A. Farooq for help with generating figure 2.

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Glossary

Multivariate analysis

The observation and analysis of more than one statistical variable at a time.

Univariate analysis

The observation and analysis of one statistical variable at a time.

Ki67

A monoclonal antibody that marks the late S phase of the cell cycle. This is frequently used to mark proliferating cells in tissues or cell suspensions.

Gleason grading system

The 'gold standard' for grading prostate cancer, used by pathologists worldwide. This system involves assessing both the predominant and secondary pattern of gland formation within a prostate sample. The sample is scored to create a Gleason 'sum', ranging from 2 to 10, with the highest number indicating the most aggressive cancer. Patients with a Gleason sum of less than 6 typically respond well to therapy, whereas patients with a Gleason sum greater than 7 usually have poor outcomes.

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Chu, I., Hengst, L. & Slingerland, J. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer 8, 253–267 (2008). https://doi.org/10.1038/nrc2347

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