Phosphorylation-dependent Regulation of Cyclin D1 Nuclear Export and Cyclin D1-dependent Cellular Transformation

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2000 Dec 22

PMID 11124803

Citations 215

Authors

J R Alt

J L Cleveland

M Hannink

J A Diehl

Affiliations

Soon will be listed here.

Abstract

GSK-3beta-dependent phosphorylation of cyclin D1 at Thr-286 promotes the nuclear-to-cytoplasmic redistribution of cyclin D1 during S phase of the cell cycle, but how phosphorylation regulates redistribution has not been resolved. For example, phosphorylation of nuclear cyclin D1 could increase its rate of nuclear export relative to nuclear import; alternatively, phosphorylation of cytoplasmic cyclin D1 by GSK-3beta could inhibit nuclear import. Here, we report that GSK-3beta-dependent phosphorylation promotes cyclin D1 nuclear export by facilitating the association of cyclin D1 with the nuclear exportin CRM1. D1-T286A, a cyclin D1 mutant that cannot be phosphorylated by GSK-3beta, remains nuclear throughout the cell cycle, a consequence of its reduced binding to CRM1. Constitutive overexpression of the nuclear cyclin D1-T286A in murine fibroblasts results in cellular transformation and promotes tumor growth in immune compromised mice. Thus, removal of cyclin D1 from the nucleus during S phase appears essential for regulated cell division.

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References

Rimerman R, Diehl J . Wnt1 and MEK1 cooperate to promote cyclin D1 accumulation and cellular transformation. J Biol Chem. 2000; 275(19):14736-42. DOI: 10.1074/jbc.m910241199. View

Sherr C, Roberts J . CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999; 13(12):1501-12. DOI: 10.1101/gad.13.12.1501. View

Resnitzky D . Apoptosis induced by ectopic expression of cyclin D1 but not cyclin E. Oncogene. 1996; 13(11):2431-7. View

Stambolic V, Ruel L, Woodgett J . Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol. 1996; 6(12):1664-8. DOI: 10.1016/s0960-9822(02)70790-2. View

Krude T, JACKMAN M, Pines J, Laskey R . Cyclin/Cdk-dependent initiation of DNA replication in a human cell-free system. Cell. 1997; 88(1):109-19. DOI: 10.1016/s0092-8674(00)81863-2. View

Todaro G, Green H . Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J Cell Biol. 1963; 17:299-313. PMC: 2106200. DOI: 10.1083/jcb.17.2.299. View

Weber J, Raben D, Phillips P, Baldassare J . Sustained activation of extracellular-signal-regulated kinase 1 (ERK1) is required for the continued expression of cyclin D1 in G1 phase. Biochem J. 1997; 326 ( Pt 1):61-8. PMC: 1218637. DOI: 10.1042/bj3260061. View

Henderson B . Nuclear-cytoplasmic shuttling of APC regulates beta-catenin subcellular localization and turnover. Nat Cell Biol. 2000; 2(9):653-60. DOI: 10.1038/35023605. View

Neufeld K, Nix D, Bogerd H, Kang Y, Beckerle M, Cullen B . Adenomatous polyposis coli protein contains two nuclear export signals and shuttles between the nucleus and cytoplasm. Proc Natl Acad Sci U S A. 2000; 97(22):12085-90. PMC: 17298. DOI: 10.1073/pnas.220401797. View

10.

Rustgi A, Dyson N, Bernards R . Amino-terminal domains of c-myc and N-myc proteins mediate binding to the retinoblastoma gene product. Nature. 1991; 352(6335):541-4. DOI: 10.1038/352541a0. View

11.

Powell S, Zilz N, Bryan T, Hamilton S, Thibodeau S, Vogelstein B . APC mutations occur early during colorectal tumorigenesis. Nature. 1992; 359(6392):235-7. DOI: 10.1038/359235a0. View

12.

Baldin V, Lukas J, Marcote M, Pagano M, Draetta G . Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 1993; 7(5):812-21. DOI: 10.1101/gad.7.5.812. View

13.

Quelle D, Ashmun R, Shurtleff S, Kato J, Bar-Sagi D, Roussel M . Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev. 1993; 7(8):1559-71. DOI: 10.1101/gad.7.8.1559. View

14.

Lees J, Saito M, Vidal M, Valentine M, Look T, Harlow E . The retinoblastoma protein binds to a family of E2F transcription factors. Mol Cell Biol. 1993; 13(12):7813-25. PMC: 364853. DOI: 10.1128/mcb.13.12.7813-7825.1993. View

15.

Resnitzky D, Gossen M, Bujard H, Reed S . Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. Mol Cell Biol. 1994; 14(3):1669-79. PMC: 358525. DOI: 10.1128/mcb.14.3.1669-1679.1994. View

16.

Nishi K, Yoshida M, Fujiwara D, Nishikawa M, Horinouchi S, Beppu T . Leptomycin B targets a regulatory cascade of crm1, a fission yeast nuclear protein, involved in control of higher order chromosome structure and gene expression. J Biol Chem. 1994; 269(9):6320-4. View

17.

Bodrug S, Warner B, Bath M, Lindeman G, Harris A, Adams J . Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. EMBO J. 1994; 13(9):2124-30. PMC: 395065. DOI: 10.1002/j.1460-2075.1994.tb06488.x. View

18.

Wang T, Cardiff R, Zukerberg L, Lees E, Arnold A, SCHMIDT E . Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature. 1994; 369(6482):669-71. DOI: 10.1038/369669a0. View

19.

Rodriguez-Viciana P, Warne P, Dhand R, Vanhaesebroeck B, Gout I, Fry M . Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994; 370(6490):527-32. DOI: 10.1038/370527a0. View

20.

Lovec H, Grzeschiczek A, Kowalski M, Moroy T . Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice. EMBO J. 1994; 13(15):3487-95. PMC: 395252. DOI: 10.1002/j.1460-2075.1994.tb06655.x. View