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Mol. Cell. Biol. doi:10.1128/MCB.00604-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The HBP1 Transcriptional Repressor Participates in RAS-Induced Premature Senescence

Dept. of Biochemistry, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. Dept. of Radiation Oncology, Tufts-New England Medical Center, 750 Washington St., Boston, MA 02111. School of Nutrition Science and Policy, Tufts University, Boston, MA. Institute for Clinical Research and Health Policy Studies, Tufts New-England Medical Center, 750 Washington St., Boston, MA 02111. Dept. of Medicine, Division of Hematology, Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross Research Building, Room 1025, Baltimore MD 21205

^* To whom correspondence should be addressed. Email: amy.yee{at}tufts.edu.

	Abstract

Oncogene-mediated premature senescence has emerged as potential tumor suppressive mechanism in early cancer transitions. Previous work shows that RAS and the p38MAPK participate in premature senescence, but transcriptional effectors have not been identified. Here, we demonstrate that the HBP1 transcriptional repressor participates in RAS and p38MAPK-induced premature senescence. In cell lines, we had previously isolated HBP1 as an RB target, but have characterized functions as a proliferation regulator by inhibiting oncogenic pathways as a transcriptional repressor. In primary cells, the results indicate that HBP1 is a necessary component of premature senescence by RAS and p38MAPK. Similarly, a knockdown of WIP1 (a p38MAPK phosphatase) induced premature senescence that also required HBP1. Furthermore, HBP1 requires regulation by RB, in which few transcriptional regulators for premature senescence have been shown. Together, the data suggest a model in which RAS and p38MAPK signaling engage HBP1 and RB to trigger premature senescence. As an initial step towards a clinical relevance, a bioinformatics approach shows that the relative expression of HBP1 and of WIP1 correlated to decreased relapse-free survival in breast cancers. Together, these studies highlight p38 MAPK, HBP1, and RB as important components for a premature senescence pathway with a possible clinical relevance to breast cancer.

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