A model of cell cycle control: Sequential events regulated by growth factors

O’Keefe, Edward J.; Pledger, W. J.

doi:10.1016/0303-7207(83)90147-8

Cited by 124 publications

(47 citation statements)

References 47 publications

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“…DISCUSSION PDGF AA and BB are equally potent growth factors in triggering the cell cycle entry. However, only PDGF AA is a bona fide "competent factor," which requires a progression factor to complete the cell cycle transition, whereas PDGF BB can serve as both competent and progression factors (32)(33)(34)(35). Our previous and present studies may provide an explanation for PDGF AA-and BB-mediated differential regulation of cell cycle at the molecular levels.…”

Section: Waf1/cip1supporting

confidence: 48%

Platelet-derived Growth Factor (PDGF) Receptor-α-activated c-Jun NH2-terminal Kinase-1 Is Critical for PDGF-induced p21 Promoter Activity Independent of p53

Liu

Kim

2003

Journal of Biological Chemistry

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Platelet-derived growth factor (PDGF) is a potent mitogen for mesenchymal cells. PDGF AA functions as a "competent factor" that stimulates cell cycle entry but requires additional (progression) factors in serum to transit the cell cycle beyond the G 1 /S checkpoint. Unlike PDGF AA, PDGF B-chain (c-sis) homodimer (PDGF BB) and its viral counterpart v-sis can serve as both competent and progression factors. PDGF BB activates ␣-and ␤-receptor subunits (␣-PDGFR and ␤-PDGFR) and induces phenotypic transformation in NIH 3T3 cells, whereas PDGF AA activates ␣-PDGFR only and fails to induce transformation. We showed previously that ␣-PDGFR antagonizes ␤-PDGFR-mediated transformation through activation of stress-activated protein kinase-1/c-Jun NH 2 -terminal kinase-1, whereas both ␣-PDGFR and ␤-PDGFR induce mitogenic signals. These studies revealed a striking feature of PDGF signaling; the specificity and the strength of the PDGF growth signal is modulated by ␣-PDGFR-mediated simultaneous activation of growth stimulatory and inhibitory signals, whereas ␤-PDGFR mainly induces a growthpromoting signal. Here we demonstrate that PDGF BB activation of ␤-PDGFR alone results in more efficient cell cycle transition from G 1 to S phase than PDGF BB activation of both ␣-PDGFR and ␤-PDGFR. PDGF AA activation of ␣-PDGFR or PDGF BB activation of both ␣-and ␤-PDGFRs up-regulates expression of p21, an inhibitor of cell cycle-dependent kinases and a downstream mediator of the tumor suppressor gene product p53. However, ␤-PDGFR activation alone fails to induce p21 WAF1/CIP1 expression. We also demonstrate that ␣-PDGFR-activated JNK-1 is a critical signaling component for PDGF induction of p21 WAF1/CIP1 promoter activity. The ability of PDGF/JNK-1 to induce p21 WAF1/CIP1 promoter activity is independent of p53, although the overall p21 WAF1/CIP1 promoter activities are greatly reduced in the absence of p53. These results provide a molecular basis for differential regulation of the cell cycle and transformation by ␣-and ␤-PDGFRs.

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Section: Waf1/cip1supporting

confidence: 48%

Platelet-derived Growth Factor (PDGF) Receptor-α-activated c-Jun NH2-terminal Kinase-1 Is Critical for PDGF-induced p21 Promoter Activity Independent of p53

Liu

Kim

2003

Journal of Biological Chemistry

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“…This explains why mitogen or CDK2 is still required for cell cycle progression in Rb abrogated cells, 5,8,17 or why hypoxia-induced p27 arrests Rb negative cells in G 1 phase. 42 p27 suppression alone without mitogen stimulation was insufficient to induce S phase in quiescent NIH3T3 cells, indicating that mitogen triggers multiple events, [43][44][45][46][47] including the cyclin D1/Rb/E2F pathway, which are necessary for passage through the restriction point. However, among these essential events, p27 suppression might be the last critical event required for passing through the restriction point Figure 5.…”

Section: Discussionmentioning

confidence: 99%

p27Kip1 and Cyclin Dependent Kinase 2 Regulate Passage Through the Restriction Point

Hitomi¹,

Ke²,

Guo³

et al. 2006

Cell Cycle

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When quiescent cells are stimulated to reenter the cell cycle, growth factors are required only until the restriction point in G 1 phase. After this point the cell no longer requires growth factors, proliferative signaling molecules, or even protein synthesis in order to initiate DNA synthesis, which starts several hours later. Consequently, understanding the molecular nature of the restriction point constitutes one of the major goals in studies of growth regulation. We recently demonstrated that p27Kip1 (p27) regulates passage through G 1 phase in actively proliferating cultures, and initiated these studies to determine if it is also involved in passage through the restriction point following stimulation of quiescent cells. In support of this suggestion, we found that passage through the restriction point requires mitogen-dependent suppression of the high p27 levels normally present in quiescent cells. Moreover, as the culture progresses to mid-G 1 phase, the proportion of cells that pass the restriction point is increased by artificial suppression of p27 levels, while this proportion is reduced by elevation of p27 levels. p27 performs this critical function by regulating the subsequent activating phosphorylation of cyclin dependent kinase (CDK)2, which we also show is necessary for and closely associated with the initiation of DNA synthesis. We conclude that the p27 expression level at mid-G 1 phase determines when a cell passes through the restriction point, and does so by regulating subsequent CDK2 activation.

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“…These cells become quiescent at confluence and remain arrested in G0 for more than a week but will resume a new cell cycle when placed in fresh serum-containing medium. 22 Purvalanol A added to confluent A-31 cells efficiently inhibited the residual [ 3 H]thymidine incorporation (data not shown). Observation by phase-contrast microscopy indicated that the drug did not affect the viability of the confluent A31 cells but prevented residual mitoses that were still detectable in the control cells.…”

Section: Purvalanol a Reversibly Inhibits Both G1 And G2 Phase Progrementioning

confidence: 91%

Cellular effects of purvalanol A: A specific inhibitor of cyclin‐dependent kinase activities

Villerbu

Gaben

Redeuilh

et al. 2001

Intl Journal of Cancer

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We have studied the effects of purvalanol A on the cell cycle progression, proliferation and viability. In synchronized cells, purvalanol A induced a reversible arrest the progression in G1 and G2 phase of the cell cycle, but did not prevent the completion of DNA synthesis in S-phase cells. The specificity of action of the drug was supported by the selective inhibition of the phosphorylation of cyclin-dependent kinase (cdk) substrates such as Rb and cyclin E. The cell contents of cyclins D1 and E were lower in cells incubated with purvalanol A compared to controls, but the level of the cdk inhibitory protein p21 WAF1/CIP1 was increased, indicating that the drug did not cause a general inhibition of gene expression. Purvalanol A did not inhibit transcription under cell-free conditions. This compound, however, caused an inhibition of the estradiol-induced expression of an integrated luciferase gene, suggesting that cdk or related enzymes may participate in the regulation of the activity of certain promoters. When exponentially growing cells, both mouse fibroblasts and human cancer cell lines, were incubated with purvalanol A for prolonged periods of time (24 hr After mitosis, cells stimulated by appropriate exogenous or internal signals will reinitiate their progression through G1 phase to the next round of DNA replication and mitosis. The same is true for quiescent cells, i.e., cells that have been deprived of mitogenic stimuli. The progression through the cell cycle requires the activity of protein kinases activated by cyclins, regulatory proteins whose expression is regulated by growth factor signaling and by the subsequent cellular mechanisms. Several of these cyclin-dependent kinases (cdk) have been documented. Cyclin D-activated kinases (cdk4 and cdk6) are active toward mid-G1, and cyclin E-activated cdk2 at the end of G1/entry into S-phase. Cyclin A-activated cdk2 is essentially active in the S-and G2-phases, whereas the cyclin B-activated cdk1 (cdc2) is necessary and sufficient to ensure mitosis. Cdk are characterized by a conserved PSTAIRE sequence, and their targets are serine and threonine residues followed by a proline. They are generally constitutively expressed, and for their activation they require specific phosphorylations/dephosphorylations of serine/threonine/tyrosine residues, besides the formation of a complex with an appropriate cyclin. 1,2 The regulation of cdk activities during the cell cycle is mediated by several mechanisms: (i) expression of the corresponding cyclin; (ii) activation of kinases (cdk-activating kinase, CAK, a cdk7/ cyclin H complex) and phosphatases needed for the phosphorylation/dephosphorylation of specific aminoacid residues; and (iii) binding to cdk inhibitory proteins (cdki), members of the families WAF1/CIP1/KIP1 (including p21 WAF1/CIP1 , p27 KIP1 , p57 KIP2 ) and INK (p16 INK4 , p15, p18). 3 Different cdk display definite specificities toward protein substrates. Both cdk4 and cdk2 phosphorylate the Rb protein but on different sites. 4 In addition, cdk2 activated by ...

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A model of cell cycle control: Sequential events regulated by growth factors

Cited by 124 publications

References 47 publications

Platelet-derived Growth Factor (PDGF) Receptor-α-activated c-Jun NH2-terminal Kinase-1 Is Critical for PDGF-induced p21 Promoter Activity Independent of p53

Platelet-derived Growth Factor (PDGF) Receptor-α-activated c-Jun NH2-terminal Kinase-1 Is Critical for PDGF-induced p21 Promoter Activity Independent of p53

p27Kip1 and Cyclin Dependent Kinase 2 Regulate Passage Through the Restriction Point

Cellular effects of purvalanol A: A specific inhibitor of cyclin‐dependent kinase activities

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