Pathway maps

Cell cycle_Regulation of G1/S transition (part 1)
Cell cycle_Regulation of G1/S transition (part 1)

Object List (links open in MetaCore):

p21, SMAD2, SMAD3, TGF-beta receptor type II, TGF-beta receptor type I, beta-TrCP, Cyclin D3, Cyclin D2, GSK3 beta, p16INK4, TGF-beta 1, Cyclin E, SARA, Cul1/Rbx1 E3 ligase, PP2A catalytic, Cyclin D, PP2A regulatory, p15, Cyclin A, JunB, Skp2/TrCP/ FBXW, Anaphase-promoting complex (APC), TGF-beta 2, PLK3 (CNK), SMAD4, APC/hCDH1 complex, CDK2, Cyclin D1, SP1, p70 S6 kinase1, Ubiquitin, CDK4, CDK6, RING-box protein 1, Brca1, CDC25A, Chk2, p27KIP1

Description

Regulation of G1/S transition (part 1)

DNA damage checkpoints are biochemical pathways that delay or halt cell cycle progression in response to DNA damage. Cell cycle proceeds in four phases in all somatic eukaryotic cells, G1, S, G2, and M, and one outside the cycle per se, G0 [1].

The G1/S cell cycle checkpoint controls the passage of q cell from the first 'gap' phase (G1) into the DNA synthesis phase (S). Many different stimuli exert G1/S checkpoint control, including TGF-beta, DNA damage, contact inhibition, replicative senescence, and growth factor withdrawal.

Transforming growth factor-beta 1 ( TGF-beta 1 ) [2] and transforming growth factor-beta 2 ( TGF-beta 2 ) [3] participate in regulation of the G1/S checkpoint. TGF-beta signals are transmitted by contacting two distantly related transmembrane serine/threonine kinases, named receptors I ( TGF receptor I ) and II ( TGF receptor II ). TGF-beta 1 and/or TGF-beta 2 bind directly to TGF receptor II, which is a constitutively active kinase. The bound TGF-beta factors are then recognized by TGF receptor I, which is recruited into the complex and becomes phosphorylated by TGF receptor II. Phosphorylation allows TGF receptor I to propagate the signal to downstream substrates [4].

TGF-beta signaling leads to an excitation of at least two pathways.

TGF-beta factors induce an association of its receptor with regulatory subunit of protein phosphatase-2A ( PP2A ). Concomitantly, three PP2A subunits (regulatory, structural and catalytic) lead to dephosphorylation and inactivation of ribosomal protein S6 kinase, 70kD, polypeptide 1 ( p70 kinase 1 ) [5]. Inactivated p70 kinase 1 fails to oppress activity of glycogen synthase kinase 3 beta ( GSK3 beta ). In this case, GSK3 beta phosphorylates cyclin D, making it accessible to the subsequent ubiquitination and proteosomal degradation [6]. Stimulation of GSK3 beta activity is observed also in the case of growth factor withdrawal [7].

In addition, TGF receptor I activates by phosphorylation SMAD family member 2 and 3 ( Smad2 and Smad3 ), which form complexes with SMAD family member 4 ( Smad4 ) that accumulate in the nucleus and regulate transcription of target genes [8]. Smad s stimulate transcription of proteins from INK4 ( p16INK and p15 ) and Kip/Cip ( p21 and p27KIP1 ) families of cell cycle kinase inhibitors directly or indirectly (for example, via b-Jun and SP1 transfactors). These inhibitors interfere with interactions between cyclin-dependent kinases ( CDK ) and cyclin s. Contact inhibition [9], replicative senescence [10], [11] and DNA damage [1] also may stimulate the G1/S checkpoint arrest through p15, p21 or p27KIP1.

Moreover, DNA damage leads to phosphorylation of checkpoint homologues ( Chk ). Phosphorylated Chk, in turn, inactivates by phosphorylation cell division cycle 25A phosphatase ( Cdc25A ). Lack of active Cdc25A results in the accumulation of the phosphorylated (inactive) form of Cdk2 and Cdk4, which are incapable to participate in initiation of replication [1].

Phosphorylated CDC25A may be exposed to ubiquitination by Anaphase-promoting complex ( APC ) and/or SCF E3 ubiquitin ligase complex in Smad3 -dependent manner (with following proteosomal degradation) [12].

Polo-like kinase 3 ( PLK3 ) may stimulate G1/S transition, e.g., via activation of CDC25A [13], [14].

References:

  1. Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S
    Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annual review of biochemistry 2004;73:39-85
  2. Ye L, Zhang HY, Wang H, Yang GH, Bu H, Zhang L, Wang SL
    Effects of transforming growth factor beta 1 on the growth of rhabdomyosarcoma cell line RD. Chinese medical journal 2005 Apr 20;118(8):678-86
  3. Chen KH, Harris DL, Joyce NC
    TGF-beta2 in aqueous humor suppresses S-phase entry in cultured corneal endothelial cells. Investigative ophthalmology & visual science 1999 Oct;40(11):2513-9
  4. Wrana JL, Attisano L, Wieser R, Ventura F, Massague J
    Mechanism of activation of the TGF-beta receptor. Nature 1994 Aug 4;370(6488):341-7
  5. Petritsch C, Beug H, Balmain A, Oft M
    TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest. Genes & development 2000 Dec 15;14(24):3093-101
  6. 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
  7. Weinberg RA
    The retinoblastoma protein and cell cycle control. Cell 1995 May 5;81(3):323-30
  8. Inman GJ, Nicolas FJ, Hill CS
    Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. Molecular cell 2002 Aug;10(2):283-94
  9. Noseda M, Chang L, McLean G, Grim JE, Clurman BE, Smith LL, Karsan A
    Notch activation induces endothelial cell cycle arrest and participates in contact inhibition: role of p21Cip1 repression. Molecular and cellular biology 2004 Oct;24(20):8813-22
  10. Satyanarayana A, Rudolph KL
    p16 and ARF: activation of teenage proteins in old age. The Journal of clinical investigation 2004 Nov;114(9):1237-40
  11. Stein GH, Drullinger LF, Soulard A, Dulic V
    Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Molecular and cellular biology 1999 Mar;19(3):2109-17
  12. Ray D, Terao Y, Nimbalkar D, Chu LH, Donzelli M, Tsutsui T, Zou X, Ghosh AK, Varga J, Draetta GF, Kiyokawa H
    Transforming growth factor beta facilitates beta-TrCP-mediated degradation of Cdc25A in a Smad3-dependent manner. Molecular and cellular biology 2005 Apr;25(8):3338-47
  13. Myer DL, Bahassi el M, Stambrook PJ
    The Plk3-Cdc25 circuit. Oncogene 2005 Jan 10;24(2):299-305
  14. Zimmerman WC, Erikson RL
    Polo-like kinase 3 is required for entry into S phase. Proceedings of the National Academy of Sciences of the United States of America 2007 Feb 6;104(6):1847-52