Cell cycle - Cell cycle (generic schema)

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Cell cycle regulation

All somatic eukaryotic cells proceed through four phases in cell cycle: G1 (gap phase 1) in which the cell prepares for the upcoming events of S-phase; S (synthesis phase), in which DNA is replicated; G2 (gap phase 2) in which the cell prepares for the upcoming events of M-phase; and M (mitosis), in which chromosomes are separated over two new nuclei. Progression through the cell cycle determines the rate of proliferation. Growth, repair and maintenance of organisms all rely on the regulation of the cycle.

Progress in the eukaryotic cell cycle is driven by oscillations in the activities of cyclin-dependent kinases (CDKs). CDK activity is controlled by periodic synthesis and degradation of positive regulatory subunits, Cyclins, as well as by fluctuations in levels of negative regulators, by CDK inhibitors (INK4 and/or KIP/CIP families), and by reversible phosphorylation [1].

In mammalian cells, different Cyclin/CDK complexes are involved in regulating different cell cycle transitions: Cyclin D/CDK4 (or CDK6) for G1 progression, Cyclin E/CDK2 for the G1-S transition [2], Cyclin A/CDK2 for S-phase progression [3], and Cyclin A/CDK1 [4] and Cyclin B/CDK1 [5] for entry into M-phase.

Biochemically, D-type cyclins (Cyclin D) act, in part, as regulatory subunits of CDK4 and CDK6. Cyclin D/CDK4 (or CDK6) complexes, together with Cyclin E/CDK2 phosphorylate of the retinoblastoma family of tumor suppressor proteins (Rb family) (Rb protein, p107 and p130), thereby liberating the E2F transcription factors (for example, E2F1 or E2F4) [6]. These transcription factors are associated with DP1 and together they drive expression of Cyclin E, Cyclin A, CDK1 and products that are necessary for the replication of DNA and beginning of the 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 the induction of expression of Cyclin A [7], [8].

The ability of Cyclin D to interact with and activate their CDK partners is antagonized by CDK inhibitors [2] (see map 544. Regulation of G1/S checkpoint). Participators of G1/S transition (see map On G1 to S phase transition) and DNA-damages-induced G1/S checkpoint arrest (see map 426. ATM/ATR regulation of G1/S checkpoint) pathways take part in G1-phase regulation too.

In addition, E2F1 is phosphorylated by Cyclin A/Cdk2 directly in the S phase and its phosphorylation by Cyclin A/Cdk2 may modulate its activity [3].

Progression from G2- to M-phase is driven by activation of the CDK1/Cyclin B complex within the nucleus. Accordingly, the activity of CDK1/Cyclin B complex is regulated in a spatiotemporary pattern at several levels, namely (1) at the level of transcription of Cyclin B (to a lower extent on that of CDK1); (2) at the level of regulatory CDK1 phosphorylations; (3) at the level of the subcellular distribution of Cyclin B (see maps Start of the mitosis and 441. ATM/ATR regulation of G1/S checkpoint) [5].

Events controlling cell division are governed by the degradation of different regulatory proteins by the ubiquitin-dependent pathway. Anaphase-promoting complex (APC) is a one of ubiquitin ligases, which play a very important role in the cell cycle (see map 472. Role APC in cell cycle regulation) [1], [9].

References:

  1. Hershko A, Ciechanover A
    The ubiquitin system. Annual review of biochemistry 1998;67:425-79
  2. Bernards R
    CDK-independent activities of D type cyclins. Biochimica et biophysica acta 1999 Oct 29;1424(2-3):M17-22
  3. Kitagawa M, Higashi H, Suzuki-Takahashi I, Segawa K, Hanks SK, Taya Y, Nishimura S, Okuyama A
    Phosphorylation of E2F-1 by cyclin A-cdk2. Oncogene 1995 Jan 19;10(2):229-36
  4. Li CJ, Vassilev A, DePamphilis ML
    Role for Cdk1 (Cdc2)/cyclin A in preventing the mammalian origin recognition complex's largest subunit (Orc1) from binding to chromatin during mitosis. Molecular and cellular biology 2004 Jul;24(13):5875-86
  5. Castedo M, Perfettini JL, Roumier T, Kroemer G
    Cyclin-dependent kinase-1: linking apoptosis to cell cycle and mitotic catastrophe. Cell death and differentiation 2002 Dec;9(12):1287-93
  6. 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
  7. 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
  8. Kato J
    Induction of S phase by G1 regulatory factors. Frontiers in bioscience : a journal and virtual library 1999 Dec 1;4:D787-92
  9. Castro A, Bernis C, Vigneron S, Labbe JC, Lorca T
    The anaphase-promoting complex: a key factor in the regulation of cell cycle. Oncogene 2005 Jan 13;24(3):314-25

  1. Hershko A, Ciechanover A
    The ubiquitin system. Annual review of biochemistry 1998;67:425-79
  2. Bernards R
    CDK-independent activities of D type cyclins. Biochimica et biophysica acta 1999 Oct 29;1424(2-3):M17-22
  3. Kitagawa M, Higashi H, Suzuki-Takahashi I, Segawa K, Hanks SK, Taya Y, Nishimura S, Okuyama A
    Phosphorylation of E2F-1 by cyclin A-cdk2. Oncogene 1995 Jan 19;10(2):229-36
  4. Li CJ, Vassilev A, DePamphilis ML
    Role for Cdk1 (Cdc2)/cyclin A in preventing the mammalian origin recognition complex's largest subunit (Orc1) from binding to chromatin during mitosis. Molecular and cellular biology 2004 Jul;24(13):5875-86
  5. Castedo M, Perfettini JL, Roumier T, Kroemer G
    Cyclin-dependent kinase-1: linking apoptosis to cell cycle and mitotic catastrophe. Cell death and differentiation 2002 Dec;9(12):1287-93
  6. 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
  7. 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
  8. Kato J
    Induction of S phase by G1 regulatory factors. Frontiers in bioscience : a journal and virtual library 1999 Dec 1;4:D787-92
  9. Castro A, Bernis C, Vigneron S, Labbe JC, Lorca T
    The anaphase-promoting complex: a key factor in the regulation of cell cycle. Oncogene 2005 Jan 13;24(3):314-25

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