Late Signals from the PDGF Receptors Leading to the Activation of the p70S6-Kinase Are Necessary for the Transition from G1 to S phase in AKR-2B Cells

Simm, Andreas; Hoppe, Viviane; Karbach, Doris; Leicht, Monika; Fenn, Anke; Hoppe, Jürgen

doi:10.1006/excr.1998.4200

Cited by 19 publications

(12 citation statements)

References 76 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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“…Because the mitogenic activity of PDGF has been known to depend both on Ras and p70S6K, 18 we hypothesized that one of the major indirect cellular factors might be PDGF. We thus assessed the secretion of PDGF-AA into the medium and the effect of anti-PDGF-AA neutralizing antibody (anti-PDGF-Ab) on HGF secretion in HSMCs (PDGF-B chain was not detected by ELISA; data not shown).…”

Section: Sustained Expression Of Hgf In the Later Phase Via Fgf-2 Is mentioning

confidence: 99%

Fibroblast Growth Factor-2 Gene Transfer Can Stimulate Hepatocyte Growth Factor Expression Irrespective of Hypoxia-Mediated Downregulation in Ischemic Limbs

Onimaru

Yonemitsu

Tanii

et al. 2002

Circulation Research

115

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Abstract-Hepatocyte growth factor (HGF) is a potent angiogenic polypeptide that stimulates angiogenesis. Transcriptional regulation of HGF, however, has not been fully defined, with the exception of the hypoxia-mediated downregulation in cultured cells. In the present study, we report that angiogenic growth factors, including HGF, were upregulated in a murine model of critical limb ischemia in vivo, a finding that was in conflict with previous in vitro data. Mice deficient in basic fibroblast growth factor-2 (FGF-2) showed reduced induction of HGF protein in ischemic muscles, and overexpression of FGF-2 via gene transfer stimulated endogenous HGF, irrespective of the presence of ischemia. In culture, FGF-2 rapidly stimulated HGF mRNA, and a sustained expression was evident in the time course in vascular smooth muscle cells and fibroblasts. FGF-2-mediated induction of HGF was fully dependent on the mitogen-activated protein kinase pathway yet was not affected by either hypoxia or a protein kinase A inhibitor. In the early expression, FGF-2 directly stimulated HGF mRNA without the requirement of new protein synthesis, whereas sustained induction of HGF in the later phase was partly mediated by platelet-derived growth factor-AA. Furthermore, in vivo overexpression of FGF-2 significantly improved the blood perfusion, and the effect was abolished by systemic blockade of HGF in ischemic limbs. This is the first demonstration of a regulational mechanism of HGF expression via FGF-2 that was independent of the presence of hypoxia. The harmonized therapeutic effects of FGF-2, accompanied with the activity of endogenous HGF, may provide a beneficial effect for the treatment of limb ischemia.

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“…In quiescent cells the rapid spike in Ras activity following growth factor stimulation, followed by lower levels of expression through G1 phase, are believed to both be required for cyclin D1 induction and entry into S phase. [23][24][25] In cycling cells, because Ras is constantly active, it does not appear that a sudden elevation in Ras activity is likely to account for cyclin D1 stimulation. On the other hand, a particular subset of cellular Ras proteins (for example, those localized in a particular subcellular location) might be directly involved in cyclin D1 induction.…”

Section: Resultsmentioning

confidence: 99%

Ras Is Active Throughout the Cell Cycle, but Is Able to Induce Cyclin D1 Only During G2 Phase

Sa¹,

Hitomi²,

Harwalkar³

et al. 2002

Cell Cycle

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© 2 0 0 2 L a n d e s B i o s c i e n c e . N o t f o r d i s t r i b u t i o n . ABSTRACTThe control of cell cycle progression has been studied in asynchronous cultures using image analysis and time lapse techniques. This approach allows determination of the cycle phase and signaling properties of individual cells, and avoids the need for synchronization. In past studies this approach demonstrated that continuous cell cycle progression requires the induction of cyclin D1 levels by Ras, and that this induction takes place during G2 phase. These studies were designed to understand how Ras could induce cyclin D1 levels only during G2 phase. First, in studies with a Ras-specific promoter and cellular migration we find that endogenous Ras is active in all cell cycle phases of actively cycling NIH3T3 cells. This suggests that cyclin D1 induction during G2 phase is not the result of Ras activation specifically during this cell cycle period. To confirm this suggestion oncogenic Ras, which is expected to be active in all cell cycle phases, was microinjected into asynchronous cells. The injected protein induced cyclin D1 levels rapidly, but only in G2 phase cells. We conclude that in the continuously cycling cell the targets of Ras activity are controlled by cell cycle phase, and that this phenomenon is vital to cell cycle progression.

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Late Signals from the PDGF Receptors Leading to the Activation of the p70S6-Kinase Are Necessary for the Transition from G1 to S phase in AKR-2B Cells

Cited by 19 publications

References 76 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

Fibroblast Growth Factor-2 Gene Transfer Can Stimulate Hepatocyte Growth Factor Expression Irrespective of Hypoxia-Mediated Downregulation in Ischemic Limbs

Ras Is Active Throughout the Cell Cycle, but Is Able to Induce Cyclin D1 Only During G2 Phase

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