Cell cycle - Regulation of G1/S transition (part 2)

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Regulation of G1/S transition (part 2)

The commencement of the cell cycle coincides with the production and the stabilization of the Cyclin D. The D-type cyclins are essential for synchronization of the cell cycle machinery with extracellular signals. [1] Expression and stability of Cyclin D is monitored by growth factor receptors [2], [3] and focal adhesion-mediated [4], [5] signaling pathways.. Expression of Cyclin D may be activated through MAPK-cascade (via SP1 [6], c-Fos, c-Jun [7] transfactors) and/or through AKT / IKK / NF-KB pathway [8]. In addition, AKT may inhibit GSK3 beta, thus preventing degradation of Cyclin D via the GSK3-dependent pathway [9].

Cyclins D are positive-regulatory partners of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6). Accumulating of Cyclin D/CDK complexes is activated by phosphorylation of CDKs by CAK complex [10].

CDKs inhibit retinoblastoma tumor suppressors (pRB)-family proteins (Rb protein, p107 and p130). pRB-family members are believed to function through their effects on the transcription of genes regulated by the E2F transcription factors. CDK4 or CDK6 phosphorylate pRB-family members, thereby liberating E2Fs (for example, E2F1 or E2F4) [11]. These transcription factors associate with DP1 and together they induce expression of Cyclin E, Cyclin A and some other proteins necessary for DNA replication and the beginning of S phase. Cyclin E and Cyclin A are positive-regulatory partners of cyclin-dependent kinase 2 (CDK2). It is remarkable that both Cyclin D/CDK4 (or CDK6) and Cyclin E/CDK2 are necessary for induction of expression of Cyclin A [12], [13].

Activity of CDKs and Cyclines is inhibited by cell cycle kinase inhibitors (for example, p27KIP [14] and other, see map). During transition from G1 phase to S phase, p27KIP is exposed to ubiquitin-mediated degradation by 26S proteasome [15], [16].

References:

  1. Fu M, Wang C, Li Z, Sakamaki T, Pestell RG
    Minireview: Cyclin D1: normal and abnormal functions. Endocrinology 2004 Dec;145(12):5439-47
  2. Graham NA, Asthagiri AR
    Epidermal growth factor-mediated T-cell factor/lymphoid enhancer factor transcriptional activity is essential but not sufficient for cell cycle progression in nontransformed mammary epithelial cells. The Journal of biological chemistry 2004 May 28;279(22):23517-24
  3. Yano S, Yamaguchi M, Dong RP
    EGFR tyrosine kinase inhibitor "gefitinib (Iressa)" for cancer therapy. Nippon yakurigaku zasshi. Folia pharmacologica Japonica 2003 Dec;122(6):491-7
  4. Parsons JT
    Focal adhesion kinase: the first ten years. Journal of cell science 2003 Apr 15;116(Pt 8):1409-16
  5. Cary LA, Guan JL
    Focal adhesion kinase in integrin-mediated signaling. Frontiers in bioscience : a journal and virtual library 1999 Jan 15;4:D102-13
  6. Shie JL, Chen ZY, Fu M, Pestell RG, Tseng CC
    Gut-enriched Kruppel-like factor represses cyclin D1 promoter activity through Sp1 motif. Nucleic acids research 2000 Aug 1;28(15):2969-76
  7. Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, Pestell RG
    Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. The Journal of biological chemistry 1995 Oct 6;270(40):23589-97
  8. Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin AS Jr
    NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Molecular and cellular biology 1999 Aug;19(8):5785-99
  9. Diehl JA, Cheng M, Roussel MF, Sherr CJ
    Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes & development 1998 Nov 15;12(22):3499-511
  10. Lolli G, Johnson LN
    CAK-Cyclin-dependent Activating Kinase: a key kinase in cell cycle control and a target for drugs? Cell cycle (Georgetown, Tex.) 2005 Apr;4(4):572-7
  11. Frolov MV, Dyson NJ
    Molecular mechanisms of E2F-dependent activation and pRB-mediated repression. Journal of cell science 2004 May 1;117(Pt 11):2173-81
  12. Lundberg AS, Weinberg RA
    Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Molecular and cellular biology 1998 Feb;18(2):753-61
  13. Kato J
    Induction of S phase by G1 regulatory factors. Frontiers in bioscience : a journal and virtual library 1999 Dec 1;4:D787-92
  14. Zhang W, Bergamaschi D, Jin B, Lu X
    Posttranslational modifications of p27kip1 determine its binding specificity to different cyclins and cyclin-dependent kinases in vivo. Blood 2005 May 1;105(9):3691-8
  15. Ang XL, Wade Harper J
    SCF-mediated protein degradation and cell cycle control. Oncogene 2005 Apr 18;24(17):2860-70
  16. Zhang L, Wang C
    PAX3-FKHR transformation increases 26 S proteasome-dependent degradation of p27Kip1, a potential role for elevated Skp2 expression. The Journal of biological chemistry 2003 Jan 3;278(1):27-36

  1. Fu M, Wang C, Li Z, Sakamaki T, Pestell RG
    Minireview: Cyclin D1: normal and abnormal functions. Endocrinology 2004 Dec;145(12):5439-47
  2. Graham NA, Asthagiri AR
    Epidermal growth factor-mediated T-cell factor/lymphoid enhancer factor transcriptional activity is essential but not sufficient for cell cycle progression in nontransformed mammary epithelial cells. The Journal of biological chemistry 2004 May 28;279(22):23517-24
  3. Yano S, Yamaguchi M, Dong RP
    EGFR tyrosine kinase inhibitor "gefitinib (Iressa)" for cancer therapy. Nippon yakurigaku zasshi. Folia pharmacologica Japonica 2003 Dec;122(6):491-7
  4. Parsons JT
    Focal adhesion kinase: the first ten years. Journal of cell science 2003 Apr 15;116(Pt 8):1409-16
  5. Cary LA, Guan JL
    Focal adhesion kinase in integrin-mediated signaling. Frontiers in bioscience : a journal and virtual library 1999 Jan 15;4:D102-13
  6. Shie JL, Chen ZY, Fu M, Pestell RG, Tseng CC
    Gut-enriched Kruppel-like factor represses cyclin D1 promoter activity through Sp1 motif. Nucleic acids research 2000 Aug 1;28(15):2969-76
  7. Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, Pestell RG
    Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. The Journal of biological chemistry 1995 Oct 6;270(40):23589-97
  8. Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin AS Jr
    NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Molecular and cellular biology 1999 Aug;19(8):5785-99
  9. Diehl JA, Cheng M, Roussel MF, Sherr CJ
    Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes & development 1998 Nov 15;12(22):3499-511
  10. Lolli G, Johnson LN
    CAK-Cyclin-dependent Activating Kinase: a key kinase in cell cycle control and a target for drugs? Cell cycle (Georgetown, Tex.) 2005 Apr;4(4):572-7
  11. Frolov MV, Dyson NJ
    Molecular mechanisms of E2F-dependent activation and pRB-mediated repression. Journal of cell science 2004 May 1;117(Pt 11):2173-81
  12. Lundberg AS, Weinberg RA
    Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Molecular and cellular biology 1998 Feb;18(2):753-61
  13. Kato J
    Induction of S phase by G1 regulatory factors. Frontiers in bioscience : a journal and virtual library 1999 Dec 1;4:D787-92
  14. Zhang W, Bergamaschi D, Jin B, Lu X
    Posttranslational modifications of p27kip1 determine its binding specificity to different cyclins and cyclin-dependent kinases in vivo. Blood 2005 May 1;105(9):3691-8
  15. Ang XL, Wade Harper J
    SCF-mediated protein degradation and cell cycle control. Oncogene 2005 Apr 18;24(17):2860-70
  16. Zhang L, Wang C
    PAX3-FKHR transformation increases 26 S proteasome-dependent degradation of p27Kip1, a potential role for elevated Skp2 expression. The Journal of biological chemistry 2003 Jan 3;278(1):27-36

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