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J. Biol. Chem., Vol. 278, Issue 49, 49582-49588, December 5, 2003

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Platelet-derived Growth Factor (PDGF) Receptor--activated c-Jun NH₂-terminal Kinase-1 Is Critical for PDGF-induced p21^WAF1/CIP1 Promoter Activity Independent of p53^*

Jiuhong Yu, Xu-Wen Liu, and Hyeong-Reh Choi Kim

From the Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201

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 - 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 NH₂-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 growth-promoting signal. Here we demonstrate that PDGF BB activation of -PDGFR alone results in more efficient cell cycle transition from G₁ 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^WAF1/CIP1, 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.

Received for publication, September 8, 2003

^* This work is supported by NCI Grant CA64139 from the National Institutes of Health (to H-R. C. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pathology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201. Tel.: 313-577-2407 or 577-0193; Fax: 313-577-9165; E-mail: hrckim{at}med.wayne.edu.

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