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Mol Cell Biol. Mar 1994; 14(3): 2066–2076.
PMCID: PMC358567

D-type cyclin-dependent kinase activity in mammalian cells.

Abstract

D-type cyclin-dependent kinase activities have not so far been detected in mammalian cells. Lysis of rodent fibroblasts, mouse macrophages, or myeloid cells with Tween 20 followed by precipitation with antibodies to cyclins D1, D2, and D3 or to their major catalytic partner, cyclin-dependent kinase 4 (cdk4), yielded kinase activities in immune complexes which readily phosphorylated the retinoblastoma protein (pRb) but not histone H1 or casein. Virtually all cyclin D1-dependent kinase activity in proliferating macrophages and fibroblasts could be attributed to cdk4. When quiescent cells were stimulated by growth factors to enter the cell cycle, cyclin D1-dependent kinase activity was first detected in mid G1, reached a maximum near the G1/S transition, and remained elevated in proliferating cells. The rate of appearance of kinase activity during G1 phase lagged significantly behind cyclin induction and correlated with the more delayed accumulation of cdk4 and formation of cyclin D1-cdk4 complexes. Thus, cyclin D1-associated kinase activity was not detected during the G0-to-G1 transition, which occurs within the first few hours following growth factor stimulation. Rodent fibroblasts engineered to constitutively overexpress either cyclin D1 alone or cyclin D3 together with cdk4 exhibited greatly elevated cyclin D-dependent kinase activity, which remained absent in quiescent cells but rose to supraphysiologic levels as cells progressed through G1. Therefore, despite continued enforced overproduction of cyclins and cdk4, the assembly of cyclin D-cdk4 complexes and the appearance of their kinase activities remained dependent upon serum stimulation, indicating that upstream regulators must govern formation of the active enzymes.

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  • Ajchenbaum F, Ando K, DeCaprio JA, Griffin JD. Independent regulation of human D-type cyclin gene expression during G1 phase in primary human T lymphocytes. J Biol Chem. 1993 Feb 25;268(6):4113–4119. [PubMed]
  • Anderson SJ, Gonda MA, Rettenmier CW, Sherr CJ. Subcellular localization of glycoproteins encoded by the viral oncogene v-fms. J Virol. 1984 Sep;51(3):730–741. [PMC free article] [PubMed]
  • Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 1993 May;7(5):812–821. [PubMed]
  • Bates S, Bonetta L, MacAllan D, Parry D, Holder A, Dickson C, Peters G. 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):71–79. [PubMed]
  • Carbonaro-Hall D, Williams R, Wu L, Warburton D, Zeichner-David M, MacDougall M, Tolo V, Hall F. G1 expression and multistage dynamics of cyclin A in human osteosarcoma cells. Oncogene. 1993 Jun;8(6):1649–1659. [PubMed]
  • Desai D, Gu Y, Morgan DO. Activation of human cyclin-dependent kinases in vitro. Mol Biol Cell. 1992 May;3(5):571–582. [PMC free article] [PubMed]
  • Dowdy SF, Hinds PW, Louie K, Reed SI, Arnold A, Weinberg RA. Physical interaction of the retinoblastoma protein with human D cyclins. Cell. 1993 May 7;73(3):499–511. [PubMed]
  • Downing JR, Rettenmier CW, Sherr CJ. Ligand-induced tyrosine kinase activity of the colony-stimulating factor 1 receptor in a murine macrophage cell line. Mol Cell Biol. 1988 Apr;8(4):1795–1799. [PMC free article] [PubMed]
  • Downing JR, Shurtleff SA, Sherr CJ. Peptide antisera to human colony-stimulating factor 1 receptor detect ligand-induced conformational changes and a binding site for phosphatidylinositol 3-kinase. Mol Cell Biol. 1991 May;11(5):2489–2495. [PMC free article] [PubMed]
  • Dulić V, Lees E, Reed SI. Association of human cyclin E with a periodic G1-S phase protein kinase. Science. 1992 Sep 25;257(5078):1958–1961. [PubMed]
  • Elledge SJ, Richman R, Hall FL, Williams RT, Lodgson N, Harper JW. CDK2 encodes a 33-kDa cyclin A-associated protein kinase and is expressed before CDC2 in the cell cycle. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2907–2911. [PMC free article] [PubMed]
  • Ewen ME, Sluss HK, Sherr CJ, Matsushime H, Kato J, Livingston DM. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell. 1993 May 7;73(3):487–497. [PubMed]
  • Ewen ME, Sluss HK, Whitehouse LL, Livingston DM. TGF beta inhibition of Cdk4 synthesis is linked to cell cycle arrest. Cell. 1993 Sep 24;74(6):1009–1020. [PubMed]
  • Fesquet D, Labbé JC, Derancourt J, Capony JP, Galas S, Girard F, Lorca T, Shuttleworth J, Dorée M, Cavadore JC. The MO15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (CDKs) through phosphorylation of Thr161 and its homologues. EMBO J. 1993 Aug;12(8):3111–3121. [PMC free article] [PubMed]
  • Greenberger JS, Sakakeeny MA, Humphries RK, Eaves CJ, Eckner RJ. Demonstration of permanent factor-dependent multipotential (erythroid/neutrophil/basophil) hematopoietic progenitor cell lines. Proc Natl Acad Sci U S A. 1983 May;80(10):2931–2935. [PMC free article] [PubMed]
  • Hall FL, Williams RT, Wu L, Wu F, Carbonaro-Hall DA, Harper JW, Warburton D. Two potentially oncogenic cyclins, cyclin A and cyclin D1, share common properties of subunit configuration, tyrosine phosphorylation and physical association with the Rb protein. Oncogene. 1993 May;8(5):1377–1384. [PubMed]
  • Heald R, McLoughlin M, McKeon F. Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated Cdc2 kinase. Cell. 1993 Aug 13;74(3):463–474. [PubMed]
  • Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ. 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):331–342. [PubMed]
  • Kato JY, Sherr CJ. 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):11513–11517. [PMC free article] [PubMed]
  • Kiyokawa H, Busquets X, Powell CT, Ngo L, Rifkind RA, Marks PA. Cloning of a D-type cyclin from murine erythroleukemia cells. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2444–2447. [PMC free article] [PubMed]
  • Koff A, Cross F, Fisher A, Schumacher J, Leguellec K, Philippe M, Roberts JM. Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family. Cell. 1991 Sep 20;66(6):1217–1228. [PubMed]
  • Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR, Roberts JM. Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science. 1992 Sep 18;257(5077):1689–1694. [PubMed]
  • Koff A, Ohtsuki M, Polyak K, Roberts JM, Massagué J. Negative regulation of G1 in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-beta. Science. 1993 Apr 23;260(5107):536–539. [PubMed]
  • Lew DJ, Dulić V, Reed SI. Isolation of three novel human cyclins by rescue of G1 cyclin (Cln) function in yeast. Cell. 1991 Sep 20;66(6):1197–1206. [PubMed]
  • Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK, Roussel MF, Sherr CJ. Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell. 1992 Oct 16;71(2):323–334. [PubMed]
  • Matsushime H, Roussel MF, Ashmun RA, Sherr CJ. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell. 1991 May 17;65(4):701–713. [PubMed]
  • Matsushime H, Roussel MF, Sherr CJ. Novel mammalian cyclins (CYL genes) expressed during G1. Cold Spring Harb Symp Quant Biol. 1991;56:69–74. [PubMed]
  • Meyerson M, Harlow E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol. 1994 Mar;14(3):2077–2086. [PMC free article] [PubMed]
  • Minshull J, Golsteyn R, Hill CS, Hunt T. The A- and B-type cyclin associated cdc2 kinases in Xenopus turn on and off at different times in the cell cycle. EMBO J. 1990 Sep;9(9):2865–2875. [PMC free article] [PubMed]
  • Motokura T, Bloom T, Kim HG, Jüppner H, Ruderman JV, Kronenberg HM, Arnold A. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature. 1991 Apr 11;350(6318):512–515. [PubMed]
  • Motokura T, Keyomarsi K, Kronenberg HM, Arnold A. Cloning and characterization of human cyclin D3, a cDNA closely related in sequence to the PRAD1/cyclin D1 proto-oncogene. J Biol Chem. 1992 Oct 5;267(28):20412–20415. [PubMed]
  • Ohtsubo M, Roberts JM. Cyclin-dependent regulation of G1 in mammalian fibroblasts. Science. 1993 Mar 26;259(5103):1908–1912. [PubMed]
  • Pagano M, Pepperkok R, Lukas J, Baldin V, Ansorge W, Bartek J, Draetta G. Regulation of the cell cycle by the cdk2 protein kinase in cultured human fibroblasts. J Cell Biol. 1993 Apr;121(1):101–111. [PMC free article] [PubMed]
  • Pagano M, Pepperkok R, Verde F, Ansorge W, Draetta G. Cyclin A is required at two points in the human cell cycle. EMBO J. 1992 Mar;11(3):961–971. [PMC free article] [PubMed]
  • Pardee AB. G1 events and regulation of cell proliferation. Science. 1989 Nov 3;246(4930):603–608. [PubMed]
  • Pines J, Hunter T. Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2. Cell. 1989 Sep 8;58(5):833–846. [PubMed]
  • Pines J, Hunter T. Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B. Nature. 1990 Aug 23;346(6286):760–763. [PubMed]
  • Pines J, Hunter T. Human cyclins A and B1 are differentially located in the cell and undergo cell cycle-dependent nuclear transport. J Cell Biol. 1991 Oct;115(1):1–17. [PMC free article] [PubMed]
  • Poon RY, Yamashita K, Adamczewski JP, Hunt T, Shuttleworth J. The cdc2-related protein p40MO15 is the catalytic subunit of a protein kinase that can activate p33cdk2 and p34cdc2. EMBO J. 1993 Aug;12(8):3123–3132. [PMC free article] [PubMed]
  • Quelle DE, Ashmun RA, Shurtleff SA, Kato JY, Bar-Sagi D, Roussel MF, Sherr CJ. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev. 1993 Aug;7(8):1559–1571. [PubMed]
  • Rosenblatt J, Gu Y, Morgan DO. Human cyclin-dependent kinase 2 is activated during the S and G2 phases of the cell cycle and associates with cyclin A. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2824–2828. [PMC free article] [PubMed]
  • Sherr CJ. Mammalian G1 cyclins. Cell. 1993 Jun 18;73(6):1059–1065. [PubMed]
  • Solomon MJ, Harper JW, Shuttleworth J. CAK, the p34cdc2 activating kinase, contains a protein identical or closely related to p40MO15. EMBO J. 1993 Aug;12(8):3133–3142. [PMC free article] [PubMed]
  • Solomon MJ, Lee T, Kirschner MW. Role of phosphorylation in p34cdc2 activation: identification of an activating kinase. Mol Biol Cell. 1992 Jan;3(1):13–27. [PMC free article] [PubMed]
  • Stanley ER. The macrophage colony-stimulating factor, CSF-1. Methods Enzymol. 1985;116:564–587. [PubMed]
  • Tushinski RJ, Stanley ER. The regulation of mononuclear phagocyte entry into S phase by the colony stimulating factor CSF-1. J Cell Physiol. 1985 Feb;122(2):221–228. [PubMed]
  • Williams RT, Wu L, Carbonaro-Hall DA, Tolo VT, Hall FL. Identification of a novel cyclin-like protein in human tumor cells. J Biol Chem. 1993 Apr 25;268(12):8871–8880. [PubMed]
  • Withers DA, Harvey RC, Faust JB, Melnyk O, Carey K, Meeker TC. Characterization of a candidate bcl-1 gene. Mol Cell Biol. 1991 Oct;11(10):4846–4853. [PMC free article] [PubMed]
  • Won KA, Xiong Y, Beach D, Gilman MZ. Growth-regulated expression of D-type cyclin genes in human diploid fibroblasts. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9910–9914. [PMC free article] [PubMed]
  • Xiong Y, Connolly T, Futcher B, Beach D. Human D-type cyclin. Cell. 1991 May 17;65(4):691–699. [PubMed]
  • Xiong Y, Zhang H, Beach D. D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell. 1992 Oct 30;71(3):505–514. [PubMed]
  • Xiong Y, Zhang H, Beach D. Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Genes Dev. 1993 Aug;7(8):1572–1583. [PubMed]

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