The Inhibitor of Cyclin-Dependent Kinase 4a/Alternative Reading Frame (INK4a/ARF) Locus Encoded Proteins p16 and p19 Repress Cyclin D1 Transcription through Distinct cis Elements
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چکیده
The Ink4a/Arf locus encodes two structurally unrelated tumor suppressor proteins, p16 and p14 (murine p19). Invariant inactivation of either the p16-cyclin D/CDK-pRb pathway and/or p53-p14 pathway occurs in most human tumors. Cyclin D1 is frequently overexpressed in breast cancer cells contributing an alternate mechanism inactivating the p16/pRb pathway. Targeted overexpression of cyclin D1 to the mammary gland is sufficient for tumorigenesis, and cyclin D1 / mice are resistant to Ras-induced mammary tumors. Recent studies suggest cyclin D1 and p16 expression are reciprocal in human breast cancers. Herein, reciprocal regulation of cyclin D1 and p16 was observed in tissues of mice mutant for the Ink4a/Arf locus. p16 and p19 inhibited DNA synthesis in MCF7 cells. p16 repressed cyclin D1 expression and transcription. Repression of cyclin D1 by p16 occurred independently of the p16-cdk4-binding function and required a cAMP-response element/activating transcription factor-2-binding site. p19 repressed cyclin D1 through a novel distal cis-element at 1137, which bound p53 in chromatin-immunoprecipitation assays. Transcriptional repression of the cyclin D1 gene through distinct DNA sequences may contribute to the tumor suppressor function of the Ink4a/ Arf locus.
منابع مشابه
The inhibitor of cyclin-dependent kinase 4a/alternative reading frame (INK4a/ARF) locus encoded proteins p16INK4a and p19ARF repress cyclin D1 transcription through distinct cis elements.
The Ink4a/Arf locus encodes two structurally unrelated tumor suppressor proteins, p16(INK4a) and p14(ARF) (murine p19(ARF)). Invariant inactivation of either the p16(INK4a)-cyclin D/CDK-pRb pathway and/or p53-p14(ARF) pathway occurs in most human tumors. Cyclin D1 is frequently overexpressed in breast cancer cells contributing an alternate mechanism inactivating the p16(INK4a)/pRb pathway. Targ...
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