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The Inhibitor of Cyclin-Dependent Kinase 4a/Alternative Reading Frame (INK4a/ARF) Locus Encoded Proteins p16^INK4a and p19^ARF Repress Cyclin D1 Transcription through Distinct cis Elements

¹ Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC; Departments of ² Pathology and ³ Molecular Pharmacology, Albert Einstein College of Medicine, Albert Einstein Cancer Center, Bronx, New York; and ⁴ Department of Cell Biology and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas

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. 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^INK4a expression are reciprocal in human breast cancers. Herein, reciprocal regulation of cyclin D1 and p16^INK4a was observed in tissues of mice mutant for the Ink4a/Arf locus. p16^INK4a and p19^ARF inhibited DNA synthesis in MCF7 cells. p16^INK4a repressed cyclin D1 expression and transcription. Repression of cyclin D1 by p16^INK4a occurred independently of the p16^INK4a-cdk4-binding function and required a cAMP-response element/activating transcription factor-2-binding site. p19^ARF 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.

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