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
| Autor: | R J, Lee, C, Albanese, R J, Stenger, G, Watanabe, G, Inghirami, G K, Haines, M, Webster, W J, Muller, J S, Brugge, R J, Davis, R G, Pestell |
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| Rok vydání: | 1999 |
| Předmět: |
Activating Transcription Factor 2
JNK Mitogen-Activated Protein Kinases Breast Neoplasms Mice Transgenic p38 Mitogen-Activated Protein Kinases Oncogene Protein pp60(v-src) Gene Expression Regulation Neoplastic Mice Calcium-Calmodulin-Dependent Protein Kinases Tumor Cells Cultured Animals Cyclin D1 Mitogen-Activated Protein Kinases Cyclic AMP Response Element-Binding Protein Promoter Regions Genetic Plasmids Protein Binding Signal Transduction Transcription Factors |
| Zdroj: | The Journal of biological chemistry. 274(11) |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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