The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases

doi:10.1016/0092-8674(93)90499-G

Cell

Volume 75, Issue 4, 19 November 1993, Pages 805-816

https://doi.org/10.1016/0092-8674(93)90499-G Get rights and content

Abstract

The cyclin-dependent kinase Cdk2 associates with cyclins A, D, and E and has been implicated in the control of the G1 to S phase transition in mammals. To identify potential Cdk2 regulators, we have employed an improved two-hybrid system to isolate human genes encoding Cdk-interacting proteins (Cips). CIP1 encodes a novel 21 kd protein that is found in cyclin A, cyclin D1, cyclin E, and Cdk2 immunoprecipitates. p21^CIP1 is a potent, tight-binding inhibitor of Cdks and can inhibit the phosphorylation of Rb by cyclin A-Cdk2, cyclin E-Cdk2, cyclin D1-Cdk4, and cyclin D2-Cdk4 complexes. Cotransfection experiments indicate that CIP1 and SV40 T antigen function in a mutually antagonistic manner to control cell cycle progression.

References (50)

V. Baldin et al.
Cyclin D1 is a nuclear protein required for cell cycle progression in G1
Genes Dev.
(1993)
F. Chang et al.
Identification of a gene necessary for cell cycle arrest by a negative growth factor of yeast: FAR1 is an inhibitor of a G1 cyclin, CLN2
Cell
(1990)
C. Chen et al.
High efficiency transformation of mammalian cells by plasmid DNA
Mol. Cell. Biol.
(1987)
L. Connell-Crowley et al.
Phosphorylation independent activation of human Cdk2 by cyclin A in vitro
Mol. Biol. Cell
(1993)
B.R. Cullen
Use of eukaryotic expression technology in the functional analysis of cloned genes
Meth. Enzymol.
(1987)
C. Dingwall et al.
Nuclear targeting sequences: a consensus?
Trends Biochem. Sci.
(1991)
Q.-P. Dou et al.
Cyclin E and cyclin A as candidates for the restriction point protein
Cancer Res.
(1993)
S.F. Dowdy et al.
Physical interaction of the retinoblastoma protein with human D cyclins
Cell
(1993)
G. Draetta et al.
Identification of p34 and p13, human homologs of the cell cycle regulators of fission yeast encoded by cdc2⁺ and suc1⁺
Cell
(1987)
V. Dulic et al.
Association of human cyclin E with a periodic G1-S phase protein kinase
Science
(1992)

T. Durfee et al.

The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit

Genes Dev.

(1993)

W.S. El-Deiry et al.

WAF1, a potential mediator of p53 tumor suppression

Cell

(1993)

S. Elledge et al.

A new human p34 protein kinase, CDK2, identified by complementation of a cdc28 mutation in Saccharomyces cerevisiae, is a homolog of the Xenopus Eg1 gene

EMBO J.

(1991)

S.J. Elledge et al.

CDK2 encodes a 33 kd cyclin A-associated protein kinase and is expressed before CDC2 in the cell cycle

M.E. Ewen et al.

Functional interactions of the retinoblastoma protein with mammalian D-type cyclins

Cell

(1993)

F. Fang et al.

Evidence that the G1-S and G2-M transitions are controlled by different cdc2 proteins in eukaryotes

Cell

(1991)

S. Fields et al.

A novel genetic system to detect protein-protein interactions

Nature

(1989)

J. Gautier et al.

Cyclin is a component of maturation-promoting factor from Xenopus

Cell

(1990)

K.L. Gould et al.

Tyrosine phosphorylation of the fission yeast cdc2 protein kinase regulates entry into mitosis

Nature

(1989)

E. Harlow et al.

P.W. Hinds et al.

Regulation of retinoblastoma protein functions by ectopic expression of human cyclins

Cell

(1992)

T. Hunt

Maturating promoting factor, cyclin, and the control of M-phase

Curr. Opin. Cell Biol.

(1989)

T. Hunter et al.

Cyclins and cancer

Cell

(1991)

J.-Y. Kato et al.

Direct binding of cyclin D to the retinoblastoma gene product and pRb phosphorylation by the cyclin D-dependent kinase cdk4

Genes Dev.

(1993)

K. Keyomarsi et al.

Redundant cyclin overexpression and gene amplification in breast cancer cells

Cited by (5444)

Cardiac-specific deletion of heat shock protein 60 induces mitochondrial stress and disrupts heart development in mice
2024, Biochemical and Biophysical Research Communications
Congenital heart diseases are the most common birth defects around the world. Emerging evidence suggests that mitochondrial homeostasis is required for normal heart development. In mitochondria, a series of molecular chaperones including heat shock protein 60 (HSP60) are engaged in assisting the import and folding of mitochondrial proteins. However, it remains largely obscure whether and how these mitochondrial chaperones regulate cardiac development. Here, we generated a cardiac-specific Hspd1 deletion mouse model by αMHC-Cre and investigated the role of HSP60 in cardiac development. We observed that deletion of HSP60 in embryonic cardiomyocytes resulted in abnormal heart development and embryonic lethality, characterized by reduced cardiac cell proliferation and thinner ventricular walls, highlighting an essential role of cardiac HSP60 in embryonic heart development and survival. Our results also demonstrated that HSP60 deficiency caused significant downregulation of mitochondrial ETC subunits and induced mitochondrial stress. Analysis of gene expression revealed that P21 that negatively regulates cell proliferation is significantly upregulated in HSP60 knockout hearts. Moreover, HSP60 deficiency induced activation of eIF2α-ATF4 pathway, further indicating the underlying mitochondrial stress in cardiomyocytes after HSP60 deletion. Taken together, our study demonstrated that regular function of mitochondrial chaperones is pivotal for maintaining normal mitochondrial homeostasis and embryonic heart development.
A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization
2024, Redox Biology
Reactive oxygen species (ROS) play a pivotal role in macrophage-mediated acute inflammation. However, the precise molecular mechanism by which ROS regulate macrophage polarization remains unclear. Here, we show that ROS function as signaling molecules that regulate M1 macrophage polarization through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (Chk2), vital effector kinases in the DNA damage response (DDR) signaling pathway. We further demonstrate that Chk2 phosphorylates PKM2 at the T95 and T195 sites, promoting glycolysis and facilitating macrophage M1 polarization. In addition, Chk2 activation increases the Chk2-dependent expression of p21, inducing cell cycle arrest for subsequent macrophage M1 polarization. Finally, Chk2-deficient mice infected with lipopolysaccharides (LPS) display a significant decrease in lung inflammation and M1 macrophage counts. Taken together, these results suggest that inhibiting the ROS-Chk2 axis can prevent the excessive inflammatory activation of macrophages, and this pathway can be targeted to develop a novel therapy for inflammation-associated diseases and expand our understanding of the pathophysiological functions of DDR in innate immunity.
Novel pyrano[2,3-c]pyrazolopyrimidines as promising anticancer agents: Design, synthesis, and cell cycle arrest of HepG2 cells at S phase
2024, Synthetic Communications
The poor selectivity, significant toxicity, high cost, and emergence of resistance of conventional chemotherapies are driving motive for the ongoing search for novel anticancer agents. New pyrano[2,3-c]pyrazolopyrimidines were synthesized and examined as antiproliferative agents, and the possible molecular mechanism(s) of action were explored. The mass and elemental analyses, alongside the IR,¹H, and ¹³C NMR spectra, confirmed the proposed structures of the obtained compounds. Derivatives 4 and 7 demonstrated the best antiproliferative profile against HepG2 cancer cells at 4 µM, with a high selectivity index of ∼7–9 folds. They increased the S phase cell population by 51% and 40% and caused a 5- and 11-fold increase in the p21 protein. Compound 7 was superior in inhibiting HepG2 cell migration and delayed wound healing, reducing migration rates by 55% and 90%, respectively. Future studies on the pharmacokinetics, pharmacodynamics, antimetastatic, and antitumor activities in animal models would be a robust advance.
The Origin and Fate of Liver Myofibroblasts
2024, Cellular and Molecular Gastroenterology and Hepatology
Liver fibrosis of different etiologies is a serious health problem worldwide. There is no effective therapy available for liver fibrosis except the removal of the underlying cause of injury or liver transplantation. Development of liver fibrosis is caused by fibrogenic myofibroblasts that are not present in the normal liver, but rather activate from liver resident mesenchymal cells in response to chronic toxic or cholestatic injury. Many studies indicate that liver fibrosis is reversible when the causative agent is removed. Regression of liver fibrosis is associated with the disappearance of activated myofibroblasts and resorption of the fibrous scar. In this review, we discuss the results of genetic tracing and cell fate mapping of hepatic stellate cells and portal fibroblasts, their specific characteristics, and potential phenotypes. We summarize research progress in the understanding of the molecular mechanisms underlying the development and reversibility of liver fibrosis, including activation, apoptosis, and inactivation of myofibroblasts.
Compound AC1Q3QWB upregulates CDKN1A and SOX17 by interrupting the HOTAIR—EZH2 interaction and enhances the efficacy of tazemetostat in endometrial cancer
2023, Cancer Letters
Endometrial cancer (EC) is a common malignancy of the female reproductive system, with an escalating incidence. Recurrent/metastatic EC presents a poor prognosis. The interaction between the long non-coding RNA (lncRNA) HOTAIR and the polycomb repressive complex 2 (PRC2) induces abnormal silencing of tumor suppressor genes, exerting a pivotal role in tumorigenesis. We have previously discovered AC1Q3QWB (AQB), a small-molecule compound targeting HOTAIR-EZH2 interaction. In the present study, we unveil that AQB selectively hampers the interaction between HOTAIR and EZH2 within EC cells, thus reversing the epigenetic suppression of tumor suppressor genes. Furthermore, our findings demonstrate AQB's synergistic effect with tazemetostat (TAZ), an EZH2 inhibitor, significantly boosting the expression of CDKN1A and SOX17. This, in turn, induces cell cycle arrest and impedes EC cell proliferation, migration, and invasion. In vivo experiments further validate AQB's potential by enhancing TAZ's anti-tumor efficacy at lower doses. Our results advocate AQB, a recently discovered small-molecule inhibitor, as a promising agent against EC cells. When combined with TAZ, it offers a novel therapeutic strategy for EC treatment.
CIP/KIP and INK4 families as hostages of oncogenic signaling
2024, Cell Division

View all citing articles on Scopus

View full text

Cell

ArticleThe p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases

Abstract

Cyclin D1 is a nuclear protein required for cell cycle progression in G1

Genes Dev.

Identification of a gene necessary for cell cycle arrest by a negative growth factor of yeast: FAR1 is an inhibitor of a G1 cyclin, CLN2

Cell

High efficiency transformation of mammalian cells by plasmid DNA

Mol. Cell. Biol.

Phosphorylation independent activation of human Cdk2 by cyclin A in vitro

Mol. Biol. Cell

Use of eukaryotic expression technology in the functional analysis of cloned genes

Meth. Enzymol.

Nuclear targeting sequences: a consensus?

Trends Biochem. Sci.

Cyclin E and cyclin A as candidates for the restriction point protein

Cancer Res.

Physical interaction of the retinoblastoma protein with human D cyclins

Cell

Identification of p34 and p13, human homologs of the cell cycle regulators of fission yeast encoded by cdc2+ and suc1+

Cell

Association of human cyclin E with a periodic G1-S phase protein kinase

Science

The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit

Genes Dev.

WAF1, a potential mediator of p53 tumor suppression

Cell

A new human p34 protein kinase, CDK2, identified by complementation of a cdc28 mutation in Saccharomyces cerevisiae, is a homolog of the Xenopus Eg1 gene

EMBO J.

CDK2 encodes a 33 kd cyclin A-associated protein kinase and is expressed before CDC2 in the cell cycle

Functional interactions of the retinoblastoma protein with mammalian D-type cyclins

Cell

Evidence that the G1-S and G2-M transitions are controlled by different cdc2 proteins in eukaryotes

Cell

A novel genetic system to detect protein-protein interactions

Nature

Cyclin is a component of maturation-promoting factor from Xenopus

Cell

Tyrosine phosphorylation of the fission yeast cdc2 protein kinase regulates entry into mitosis

Nature

Regulation of retinoblastoma protein functions by ectopic expression of human cyclins

Cell

Maturating promoting factor, cyclin, and the control of M-phase

Curr. Opin. Cell Biol.

Cyclins and cancer

Cell

Direct binding of cyclin D to the retinoblastoma gene product and pRb phosphorylation by the cyclin D-dependent kinase cdk4

Genes Dev.

Redundant cyclin overexpression and gene amplification in breast cancer cells

Article
The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases

Identification of p34 and p13, human homologs of the cell cycle regulators of fission yeast encoded by cdc2⁺ and suc1⁺