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PMID: 10490638 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kip1) activity.

Molecular and cellular biology ·Vol. 19 ·No. 10 ·1999-10-00 ·Pages 7011-9

Tsutsui T, Hesabi B, Moons DS, Pandolfi PP, Hansel KS, Koff A, Kiyokawa H

Abstract

The mechanism by which cyclin-dependent kinase 4 (CDK4) regulates cell cycle progression is not entirely clear. Cyclin D/CDK4 appears to initiate phosphorylation of retinoblastoma protein (Rb) leading to inactivation of the S-phase-inhibitory action of Rb. However, cyclin D/CDK4 has been postulated to act in a noncatalytic manner to regulate the cyclin E/CDK2-inhibitory activity of p27(Kip1) by sequestration. In this study we investigated the roles of CDK4 in cell cycle regulation by targeted disruption of the mouse CDK4 gene. CDK4(-/-) mice survived embryogenesis and showed growth retardation and reproductive dysfunction associated with hypoplastic seminiferous tubules in the testis and perturbed corpus luteum formation in the ovary. These phenotypes appear to be opposite to those of p27-deficient mice such as gigantism and gonadal hyperplasia. A majority of CDK4(-/-) mice developed diabetes mellitus by 6 weeks, associated with degeneration of pancreatic islets. Fibroblasts from CDK4(-/-) mouse embryos proliferated similarly to wild-type embryonic fibroblasts under conditions that promote continuous growth. However, quiescent CDK4(-/-) fibroblasts exhibited a substantial ( approximately 6-h) delay in S-phase entry after serum stimulation. This cell cycle perturbation by CDK4 disruption was associated with increased binding of p27 to cyclin E/CDK2 and diminished activation of CDK2 accompanied by impaired Rb phosphorylation. Importantly, fibroblasts from CDK4(-/-) p27(-/-) embryos displayed partially restored kinetics of the G(0)-S transition, indicating the significance of the sequestration of p27 by CDK4. These results suggest that at least part of CDK4's participation in the rate-limiting mechanism for the G(0)-S transition consists of controlling p27 activity.

MeSH Terms
Animals Atrophy Cell Cycle/genetics Cell Cycle Proteins Corpus Luteum/pathology Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase 6 Cyclin-Dependent Kinase Inhibitor p27 Cyclin-Dependent Kinases/genetics,metabolism Diabetes Mellitus Female Glycosuria Homozygote Male Mice Mice, Mutant Strains Microtubule-Associated Proteins/genetics,metabolism Protein Binding Protein Serine-Threonine Kinases/analysis Proto-Oncogene Proteins Seminiferous Tubules/pathology Tissue Distribution Tumor Suppressor Proteins
Chemicals
Cdkn1b protein, mouse Cell Cycle Proteins Microtubule-Associated Proteins Proto-Oncogene Proteins Tumor Suppressor Proteins Cyclin-Dependent Kinase Inhibitor p27 Protein Serine-Threonine Kinases Cdk4 protein, mouse Cdk6 protein, mouse Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase 6 Cyclin-Dependent Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Tsutsui T
Department of Molecular Genetics, Cancer Center, University of Illinois College of Medicine, Chicago, Illinois 60607, USA.
Hesabi B
Moons D S
Pandolfi P P
Hansel K S
Koff A
Kiyokawa H
References (62)
62 references, click to expand
  1. G1 events and regulation of cell proliferation.
    Science. 1989 Nov 3;246(4930):603-8 PMID: 2683075
  2. Regulation of G1/S transition by cyclins D2 and D3 in hematopoietic cells.
    Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9571-5 PMID: 8415743
  3. Cyclin A is required at two points in the human cell cycle.
    EMBO J. 1992 Mar;11(3):961-71 PMID: 1312467
  4. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins.
    Cell. 1992 Sep 18;70(6):993-1006 PMID: 1388095
  5. Cell cycle regulation of CDK2 activity by phosphorylation of Thr160 and Tyr15.
    EMBO J. 1992 Nov;11(11):3995-4005 PMID: 1396589
  6. Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins.
    Cell. 1992 Oct 16;71(2):323-34 PMID: 1423597
  7. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4.
    Genes Dev. 1993 Mar;7(3):331-42 PMID: 8449399
  8. Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20.
    Genes Dev. 1993 Nov;7(11):2071-84 PMID: 8224839
  9. Inhibition of granulocyte differentiation by G1 cyclins D2 and D3 but not D1.
    Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11513-7 PMID: 7505440
  10. CDK6 (PLSTIRE) and CDK4 (PSK-J3) are a distinct subset of the cyclin-dependent kinases that associate with cyclin D1.
    Oncogene. 1994 Jan;9(1):71-9 PMID: 8302605
  11. Identification of G1 kinase activity for cdk6, a novel cyclin D partner.
    Mol Cell Biol. 1994 Mar;14(3):2077-86 PMID: 8114739
  12. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.
    Cell. 1994 Jul 15;78(1):59-66 PMID: 8033212
  13. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.
    Nature. 1994 Sep 15;371(6494):257-61 PMID: 8078588
  14. Suppression of cyclin-dependent kinase 4 during induced differentiation of erythroleukemia cells.
    Mol Cell Biol. 1994 Nov;14(11):7195-203 PMID: 7935434
  15. Advances in the use of embryonic stem cell technology.
    Curr Opin Biotechnol. 1994 Oct;5(5):528-33 PMID: 7765468
  16. G1 phase progression: cycling on cue.
    Cell. 1994 Nov 18;79(4):551-5 PMID: 7954821
  17. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age.
    Cell. 1994 Nov 18;79(4):573-82 PMID: 7954824
  18. The retinoblastoma protein and cell cycle control.
    Cell. 1995 May 5;81(3):323-30 PMID: 7736585
  19. Ovarian cell differentiation: a cascade of multiple hormones, cellular signals, and regulated genes.
    Recent Prog Horm Res. 1995;50:223-54 PMID: 7740159
  20. Inhibitors of mammalian G1 cyclin-dependent kinases.
    Genes Dev. 1995 May 15;9(10):1149-63 PMID: 7758941
  21. Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes.
    Genes Dev. 1995 Jun 1;9(11):1340-53 PMID: 7797074
  22. Developmental biology of the pancreas.
    Development. 1995 Jun;121(6):1569-80 PMID: 7600975
  23. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta.
    Genes Dev. 1995 Aug 1;9(15):1831-45 PMID: 7649471
  24. Cyclin D1 provides a link between development and oncogenesis in the retina and breast.
    Cell. 1995 Aug 25;82(4):621-30 PMID: 7664341
  25. The retinoblastoma gene family: cousins with overlapping interests.
    Trends Genet. 1998 Jun;14(6):223-9 PMID: 9635405
  26. Animal models of type I (insulin-dependent) diabetes mellitus.
    J Pediatr Endocrinol Metab. 1998 Jan-Feb;11(1):11-9 PMID: 9642624
  27. Hormone-induced proliferation and differentiation of granulosa cells: a coordinated balance of the cell cycle regulators cyclin D2 and p27Kip1.
    Mol Endocrinol. 1998 Jul;12(7):924-40 PMID: 9658398
  28. CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis.
    Genes Dev. 1998 Sep 15;12(18):2899-911 PMID: 9744866
  29. The absence of p27Kip1, an inhibitor of G1 cyclin-dependent kinases, uncouples differentiation and growth arrest during the granulosa->luteal transition.
    Cell Growth Differ. 1998 Sep;9(9):787-94 PMID: 9751122
  30. Regulation of exit from quiescence by p27 and cyclin D1-CDK4.
    Mol Cell Biol. 1998 Nov;18(11):6605-15 PMID: 9774675
  31. Genetics of autoimmune diabetes in animal models.
    Curr Opin Immunol. 1998 Dec;10(6):704-9 PMID: 9914220
  32. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development.
    Genes Dev. 1995 Oct 1;9(19):2364-72 PMID: 7557388
  33. Redistribution of the CDK inhibitor p27 between different cyclin.CDK complexes in the mouse fibroblast cell cycle and in cells arrested with lovastatin or ultraviolet irradiation.
    Mol Biol Cell. 1995 Sep;6(9):1197-213 PMID: 8534916
  34. Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclin E-cdk2, and phosphorylation of the retinoblastoma protein.
    J Cell Biol. 1996 Apr;133(2):391-403 PMID: 8609171
  35. Regulation of the retinoblastoma protein-related protein p107 by G1 cyclin-associated kinases.
    Proc Natl Acad Sci U S A. 1996 May 14;93(10):4633-7 PMID: 8643455
  36. Tumor induction and tissue atrophy in mice lacking E2F-1.
    Cell. 1996 May 17;85(4):537-48 PMID: 8653789
  37. E2F-1 functions in mice to promote apoptosis and suppress proliferation.
    Cell. 1996 May 17;85(4):549-61 PMID: 8653790
  38. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors.
    Cell. 1996 May 31;85(5):707-20 PMID: 8646779
  39. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1).
    Cell. 1996 May 31;85(5):721-32 PMID: 8646780
  40. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice.
    Cell. 1996 May 31;85(5):733-44 PMID: 8646781
  41. Size control: the regulation of cell numbers in animal development.
    Cell. 1996 Jul 26;86(2):173-5 PMID: 8706120
  42. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway.
    J Biol Chem. 1996 Aug 23;271(34):20608-16 PMID: 8702807
  43. Formation of p27-CDK complexes during the human mitotic cell cycle.
    Cell Growth Differ. 1996 Feb;7(2):135-46 PMID: 8822197
  44. Rapamycin resistance tied to defective regulation of p27Kip1.
    Mol Cell Biol. 1996 Dec;16(12):6744-51 PMID: 8943329
  45. Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis.
    Nature. 1996 Dec 5;384(6608):470-4 PMID: 8945475
  46. The absence of p21Cip1/WAF1 alters keratinocyte growth and differentiation and promotes ras-tumor progression.
    Genes Dev. 1996 Dec 1;10(23):3065-75 PMID: 8957006
  47. The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2.
    EMBO J. 1996 Dec 16;15(24):7060-9 PMID: 9003781
  48. Oligodendrocyte precursor differentiation is perturbed in the absence of the cyclin-dependent kinase inhibitor p27Kip1.
    Genes Dev. 1997 Sep 15;11(18):2335-46 PMID: 9308962
  49. Differential interaction of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 with cyclin A-Cdk2 and cyclin D2-Cdk4.
    J Biol Chem. 1997 Oct 10;272(41):25863-72 PMID: 9325318
  50. Control of the G1/S transition.
    Cancer Surv. 1997;29:7-23 PMID: 9338094
  51. Role of the Rb/E2F pathway in cell growth control.
    J Cell Physiol. 1997 Nov;173(2):233-6 PMID: 9365528
  52. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes.
    Mol Cell Biol. 1998 Feb;18(2):753-61 PMID: 9447971
  53. Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1).
    Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1091-6 PMID: 9448290
  54. The role of cyclin D3-dependent kinase in the phosphorylation of p130 in mouse BALB/c 3T3 fibroblasts.
    J Biol Chem. 1998 Mar 13;273(11):6190-5 PMID: 9497341
  55. Gonad development: assembling the mammalian testis.
    Curr Biol. 1998 Feb 26;8(5):R175-7 PMID: 9501063
  56. Cyclin-dependent regulation of G1 in mammalian fibroblasts.
    Science. 1993 Mar 26;259(5103):1908-12 PMID: 8384376
  57. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins.
    Cell. 1993 May 7;73(3):487-97 PMID: 8343202
  58. Physical interaction of the retinoblastoma protein with human D cyclins.
    Cell. 1993 May 7;73(3):499-511 PMID: 8490963
  59. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts.
    Genes Dev. 1993 Aug;7(8):1559-71 PMID: 8339933
  60. Expression of a retinoblastoma transgene results in dwarf mice.
    Genes Dev. 1993 Sep;7(9):1654-62 PMID: 8370518
  61. TGF beta inhibition of Cdk4 synthesis is linked to cell cycle arrest.
    Cell. 1993 Sep 24;74(6):1009-20 PMID: 8402878
  62. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle.
    Cell. 1991 May 17;65(4):701-13 PMID: 1827757
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.19.10.7011
Published
1999-10-00
Pages
7011-9
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC84696
Subset
IM
Grants
NIGMS NIH HHS · R01 GM052597 · United States
NIGMS NIH HHS · GM52597 · United States
External Links
PubMed source DOI: 10.1128/MCB.19.10.7011 PMC Full Text View journal details
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