pp60(v-src) induction of cyclin D1 requires collaborative interactions between the extracellular signal-regulated kinase, p38, and Jun kinase pathways: A role for cAMP response element-binding protein and activating transcription factor-2 in pp60(v-src) signaling in breast cancer cells

Richard J. Lee, Chris Albanese, Robert J. Stenger, Genichi Watanabe, Giorgio Inghirami, George K. Haines, Marc Webster, William J. Muller, Joan S. Brugge, Roger J. Davis, Richard G. Pestell

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Abstract

The cyclin D1 gene is overexpressed in breast tumors and encodes a regulatory subunit of cyclin-dependent kinases that phosphorylate the retinoblastoma protein. pp60(c-src) activity is frequently increased in breast tumors; however, the mechanisms governing pp60(c-src) regulation of the cell cycle in breast epithelium are poorly understood. In these studies, pp60(v-src) induced cyclin D1 protein levels and promoter activity (48-fold) in MCF7 cells. Cyclin D1-associated kinase activity and protein levels were increased in mammary tumors from murine mammary tumor virus-pp60(c-src527F) transgenic mice. Optimal induction of cyclin D1 by pp60(v-src) involved the extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase members of the mitogen-activated protein kinase family. Cyclin D1 promoter activation by pp60(v-src) involved a cAMP response element-binding protein (CREB)/activating transcription factor 2 (ATF-2) binding site. Dominant negative mutants of CREB and ATF-2 but not c-Jun inhibited pp60(v-src) induction of cyclin D1. pp60(v-src) induction of CREB was blocked by the p38 inhibitor SB203580 or by mutation of CREB at Ser133. pp60(v-src) induction of ATF-2 was abolished by the c-Jun N-terminal kinase inhibitor JNK- interacting protein-1 or by mutation of ATF-2 at Thr69 and Thr71. CREB and ATF-2, which bind to a common pp60(v-src) response element, are transcriptionally activated by distinct mitogen-activated protein kinases. Induction of cyclin D1 activity by pp60(v-src) may contribute to breast tumorigenesis through phosphorylation and inactivation of the retinoblastoma protein.

Original languageEnglish
Pages (from-to)7341-7350
Number of pages10
JournalJournal of Biological Chemistry
Volume274
Issue number11
DOIs
StatePublished - 12 Mar 1999
Externally publishedYes

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