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 G1/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 alpha- and beta-receptor subunits (alpha-PDGFR
and beta-PDGFR) and induces phenotypic transformation in NIH 3T3 cells,
whereas PDGF AA activates alpha-PDGFR only and fails to induce
transformation. We previously showed that alpha-PDGFR antagonizes
beta-PDGFR-mediated transformation through activation of stress-activated
protein kinase-1/c-Jun NH2-terminal kinase-1 (SAPK1/JNK-1), while both
alpha-PDGFR and beta-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 alpha-PDGFR-mediated
simultaneous activation of growth stimulatory and inhibitory signals,
whereas beta-PDGFR mainly induces a growth promoting signal. Here, we
demonstrate that PDGF BB activation of beta-PDGFR alone results in more
efficient cell cycle transition from G1 to S phase than PDGF BB activation
of both alpha-PDGFR and beta-PDGFR. PDGF AA activation of alpha-PDGFR or
PDGF BB activation of both alpha- and beta-PDGFRs up-regulates expression
of p21(WAF1/CIP1), an inhibitor of cell cycle dependent kinases and a
downstream mediator of the tumor suppressor gene product p53. However,
beta-PDGFR activation alone fails to induce p21(WAF1/CIP1) expression. We
also demonstrate that alpha-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 alpha- and beta-PDGFRs.
PMID:
14506245 [PubMed]
