Suppression of Cell Transformation by the Cyclin-dependent Kinase Inhibitor P57KIP2 Requires Binding to Proliferating Cell Nuclear Antigen

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1998 Mar 21

PMID 9465025

Citations 49

Authors

H Watanabe

Z Q Pan

N Schreiber-Agus

R A DePinho

J Hurwitz

Y Xiong

Affiliations

Soon will be listed here.

Abstract

Proper control of the mammalian cell cycle requires the function of cyclin-dependent kinase (CDK) inhibitors. The p21 family currently includes three distinct genes, p21, p27(Kip1), and p57(Kip2), that share a common N-terminal domain for binding to and inhibiting the kinase activity of CDK-cyclin complexes. The p21 protein also binds to proliferating cell nuclear antigen (PCNA) through a separate C-terminal domain affecting DNA replication and repair. The p27 and p57 proteins also each contain unique C-terminal domains whose functions are unknown. Here we show that the human p57 protein, like p21, contains a PCNA-binding domain within its C terminus that, when separated from its N-terminal CDK-cyclin binding domain, can prevent DNA replication in vitro and S phase entry in vivo. Disruption of either CDK/cyclin or PCNA binding partially reduced p57's ability to suppress myc/RAS-mediated transformation in primary cells, while loss of both inhibitory functions completely eliminated p57's suppressive activity. Thus, control of cell cycle and suppression of cell transformation by p57 require both CDK and PCNA inhibitory activity, and disruption of either or both functions may lead to uncontrolled cell growth.

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References

Zhang P, Liegeois N, Wong C, Finegold M, Hou H, Thompson J . Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature. 1997; 387(6629):151-8. DOI: 10.1038/387151a0. View

Yan Y, Frisen J, Lee M, Massague J, Barbacid M . Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. Genes Dev. 1997; 11(8):973-83. DOI: 10.1101/gad.11.8.973. View

Hatada I, Nabetani A, Morisaki H, Xin Z, Ohishi S, Tonoki H . New p57KIP2 mutations in Beckwith-Wiedemann syndrome. Hum Genet. 1997; 100(5-6):681-3. DOI: 10.1007/s004390050573. View

Mukherjee B, Morgenbesser S, DePinho R . Myc family oncoproteins function through a common pathway to transform normal cells in culture: cross-interference by Max and trans-acting dominant mutants. Genes Dev. 1992; 6(8):1480-92. DOI: 10.1101/gad.6.8.1480. View

Schreiber-Agus N, Torres R, Horner J, Lau A, Jamrich M, DePinho R . Comparative analysis of the expression and oncogenic activities of Xenopus c-, N-, and L-myc homologs. Mol Cell Biol. 1993; 13(4):2456-68. PMC: 359566. DOI: 10.1128/mcb.13.4.2456-2468.1993. View

Xiong Y, Hannon G, Zhang H, Casso D, Kobayashi R, Beach D . p21 is a universal inhibitor of cyclin kinases. Nature. 1993; 366(6456):701-4. DOI: 10.1038/366701a0. View

Waga S, Hannon G, Beach D, Stillman B . The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature. 1994; 369(6481):574-8. DOI: 10.1038/369574a0. View

Flores-Rozas H, Kelman Z, Dean F, Pan Z, Harper J, Elledge S . Cdk-interacting protein 1 directly binds with proliferating cell nuclear antigen and inhibits DNA replication catalyzed by the DNA polymerase delta holoenzyme. Proc Natl Acad Sci U S A. 1994; 91(18):8655-9. PMC: 44665. DOI: 10.1073/pnas.91.18.8655. View

Hunter T, Pines J . Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell. 1994; 79(4):573-82. DOI: 10.1016/0092-8674(94)90543-6. View

10.

Chen J, Jackson P, Kirschner M, Dutta A . Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA. Nature. 1995; 374(6520):386-8. DOI: 10.1038/374386a0. View

11.

Hastie N . The genetics of Wilms' tumor--a case of disrupted development. Annu Rev Genet. 1994; 28:523-58. DOI: 10.1146/annurev.ge.28.120194.002515. View

12.

Lee M, Reynisdottir I, Massague J . Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev. 1995; 9(6):639-49. DOI: 10.1101/gad.9.6.639. View

13.

Matsuoka S, Edwards M, Bai C, Parker S, Zhang P, Baldini A . p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev. 1995; 9(6):650-62. DOI: 10.1101/gad.9.6.650. View

14.

Luo Y, Hurwitz J, Massague J . Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1. Nature. 1995; 375(6527):159-61. DOI: 10.1038/375159a0. View

15.

Sherr C, Roberts J . Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995; 9(10):1149-63. DOI: 10.1101/gad.9.10.1149. View

16.

Warbrick E, Lane D, Glover D, Cox L . A small peptide inhibitor of DNA replication defines the site of interaction between the cyclin-dependent kinase inhibitor p21WAF1 and proliferating cell nuclear antigen. Curr Biol. 1995; 5(3):275-82. DOI: 10.1016/s0960-9822(95)00058-3. View

17.

Pagano M, Tam S, Theodoras A, Del Sal G, Chau V, Yew P . Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 1995; 269(5224):682-5. DOI: 10.1126/science.7624798. View

18.

Hatada I, Mukai T . Genomic imprinting of p57KIP2, a cyclin-dependent kinase inhibitor, in mouse. Nat Genet. 1995; 11(2):204-6. DOI: 10.1038/ng1095-204. View

19.

Matsuoka S, Thompson J, Edwards M, Bartletta J, Grundy P, Kalikin L . Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor, p57KIP2, on chromosome 11p15. Proc Natl Acad Sci U S A. 1996; 93(7):3026-30. PMC: 39755. DOI: 10.1073/pnas.93.7.3026. View

20.

Hatada I, Ohashi H, Fukushima Y, Kaneko Y, Inoue M, Komoto Y . An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome. Nat Genet. 1996; 14(2):171-3. DOI: 10.1038/ng1096-171. View