New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment?

doi:10.1016/S0962-8924(02)00043-0

Trends in Cell Biology

Volume 13, Issue 2, February 2003, Pages 65-70

https://doi.org/10.1016/S0962-8924(02)00043-0 Get rights and content

Abstract

Cell division relies on the activation of cyclins, which bind to cyclin-dependent kinases (CDKs) to induce cell-cycle progression towards S phase and later to initiate mitosis. Since uncontrolled cyclin-dependent kinase activity is often the cause of human cancer, their function is tightly regulated by cell-cycle inhibitors such as the p21 and p27 Cip/Kip proteins. Following anti-mitogenic signals or DNA damage, p21 and p27 bind to cyclin–CDK complexes to inhibit their catalytic activity and induce cell-cycle arrest. Interestingly, recent discoveries suggest that p21 and p27 might have new activities that are unrelated to their function as CDK inhibitors. The identification of new targets of Cip/Kip proteins as well as evidence of Cip/Kip cytoplasmic relocalization have revealed unexpected functions for these proteins in the control of CDK activation, in the regulation of apoptosis and in transcriptional activation. This article discusses recent insights into these possible additional functions of p21 and p27.

Section snippets

Cip/Kip proteins as cell-cycle inhibitors

Owing to a high level of homology in their primary structure, p21 and p27 are believed to inhibit their targets through similar mechanisms. Based on structural studies [2], it is believed that an α-helix of a Cip/Kip protein initiates a first contact with the cyclin, and that a second helix then inserts deep inside the catalytic cleft of the CDK subunit, thereby blocking ATP loading. Important cdk2 conformational changes further lock the catalytic cleft in an inactive form. Surprisingly, the

Cytoplasmic Cip/Kip proteins as assembly factors

Despite their nuclear inhibitory functions, assembly of cyclin-D1–cdk4 complexes is impaired in primary fibroblasts lacking the p21 or p27 genes [5]. It is believed that Cip/Kip proteins act as a bridge between the two subunits to enhance the binding of cyclin D1 to the CDK. These proteins act as assembly factors in the cytoplasm, where they are probably anchored to cdk4 following protein synthesis and folding [5]. Moreover, cytoplasmic Cip/Kip proteins also promote the nuclear import of D-type

Cytoplasmic Cip/Kip proteins and apoptosis

p21 and p27 might use different mechanisms to regulate cell death (Fig. 2). Illustrating these functions for p21, p21 knockout in colon carcinoma cells increases the apoptotic process following DNA damage, suggesting that the pro-survival effect relies on cyclin-B–cdk1 inhibition and G2 arrest [8]. p21 also protects colorectal carcinoma and melanoma cells from prostaglandin A2- and p53-mediated apoptosis 9, 10. As p53 activates p21 transcription, this might represent a feedback mechanism to

Cytoplasmic Cip/Kip relocalization and cell transformation

Surprisingly, Cip/Kip proteins do not fit Knudson's ‘two-mutation’ criterion of tumor-suppressor genes. Whereas loss of a single allele of p27 has been reported, inactivating mutations of both copies of the p27 gene are infrequent events. Notably, heterozygous p27^+/− mice get tumors even with only one mutant allele, indicating that p27 is haplo-insufficient for tumor protection [22]. This might indicate that the ‘two-mutation’ criterion is too restrictive and that other mechanisms should also

Nuclear and cytoplasmic functions for the yeast cell-cycle inhibitor Far1

Interestingly, there are precedents in yeast of a cell-cycle inhibitor having distinct nuclear and cytoplasmic functions (reviewed in [30]). Among the yeast cell-cycle inhibitors, the activity of the Far1 protein relies on its cellular localization. Cell-cycle arrest of Saccharomyces cerevisiae is induced by Far1p following its association with the Cdc28p–Cln complex. Furthermore, Far1p plays important functions in the initiation of cell polarity. During mating, binding of the pheromone to its

Cip/Kip proteins as transcriptional cofactors

Several studies suggest that Cip/Kip proteins might function as transcriptional cofactors. p21 regulates the activity of NF-κB, STAT3, Myc, C/EBP and E2F 35, 36, 37, and its expression inhibits several genes involved in cell-cycle progression such as those encoding DNA polymerase α, topoisomerase II, cyclin B1 and cdk1 [12]. Moreover, p21 interacts with the histone acetylase CBP/p300 [38], suggesting that it might function as a global regulator of CBP-dependent promoters through the regulation

Concluding remarks

Cip/Kip proteins clearly participate in unexpected regulatory pathways and should not be considered merely as CDK inhibitors. Cip/Kip proteins might act as cytoplasmic regulators of nuclear import, apoptosis and cell motility and they might function as transcriptional regulators in the nucleus. Although activated CDKs are probably nuclear, it will be important to confirm that these new roles are not indirectly mediated by their kinase activity and to determine whether they are always shared by

Acknowledgements

Owing to space limitations, I apologize to authors whose contributions are not listed. I would appreciate input on relevant information that I might have overlooked. This work was supported by grants and fellowships from the Ligue Nationale Pour la Recherche Sur le Cancer and the Agence Nationale de Recherche sur le SIDA.

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Trends in Cell Biology

New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment?

Abstract

Section snippets

Cip/Kip proteins as cell-cycle inhibitors

Cytoplasmic Cip/Kip proteins as assembly factors

Cytoplasmic Cip/Kip proteins and apoptosis

Cytoplasmic Cip/Kip relocalization and cell transformation

Nuclear and cytoplasmic functions for the yeast cell-cycle inhibitor Far1

Cip/Kip proteins as transcriptional cofactors

Concluding remarks

Acknowledgements

J. Biol. Chem.

Mol. Cell

Exp. Cell Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

CDK inhibitors: positive and negative regulators of G1-phase progression

Genes Dev.

Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A–Cdk2 complex

Nature

Paradigms of growth control: relation to Cdk activation

Sci. STKE

Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27

EMBO J.

The p21(Cip1) and p27(Kip1) CDK ‘inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts

EMBO J.

Cyclin E-mediated elimination of p27 requires its interaction with the nuclear pore-associated protein mNPAP60

EMBO J.

Requirement for p53 and p21 to sustain G2 arrest after DNA damage

Science

Protective role of p21(Waf1/Cip1) against prostaglandin A2-mediated apoptosis of human colorectal carcinoma cells

Mol. Cell. Biol.

p21(Waf1/Cip1) protects against p53-mediated apoptosis of human melanoma cells

Oncogene

Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage

Nature

Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases

Proc. Natl. Acad. Sci. U. S. A.

Apoptosis inhibitory activity of cytoplasmic p21(Cip1/WAF1) in monocytic differentiation

EMBO J.

Cytoplasmic p21(Cip1/WAF1) regulates neurite remodeling by inhibiting Rho-kinase activity

J. Cell Biol.

A non-enzymatic p21 protein inhibitor of stress-activated protein kinases

Nature