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Molecular and Cellular Biology, November 2006, p. 8252-8266, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00604-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The HBP1 Transcriptional Repressor Participates in RAS-Induced Premature Senescence{triangledown},{dagger}

Xiaowei Zhang,1 Jiyoung Kim,1,3 Robin Ruthazer,4 Michael A. McDevitt,5 David E. Wazer,2 K. Eric Paulson,1,2 and Amy S. Yee1*

Dept. of Biochemistry, Tufts University School of Medicine, 136 Harrison Ave., Boston, Massachusetts 02111,1 Dept. of Radiation Oncology, Tufts-New England Medical Center, 750 Washington St., Boston, Massachusetts 02111,2 School of Nutrition Science and Policy, Tufts University,Boston, Massachusetts,3 Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, 750 Washington St., Boston, Massachusetts 02111,4 Dept. of Medicine, Division of Hematology, Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross Research Building, Room 1025, Baltimore, Maryland 212055

Received 7 April 2006/ Returned for modification 5 May 2006/ Accepted 17 August 2006

Oncogene-mediated premature senescence has emerged as a potential tumor-suppressive mechanism in early cancer transitions. Previous work shows that RAS and p38 MAPK participate in premature senescence, but transcriptional effectors have not been identified. Here, we demonstrate that the HBP1 transcriptional repressor participates in RAS- and p38 MAPK-induced premature senescence. In cell lines, we had previously isolated HBP1 as a retinoblastoma (RB) target but have determined that it 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 p38 MAPK. Similarly, a knockdown of WIP1 (a p38 MAPK 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 p38 MAPK signaling engage HBP1 and RB to trigger premature senescence. As an initial step toward clinical relevance, a bioinformatics approach shows that the relative expression levels of HBP1 and WIP1 correlated with decreased relapse-free survival in breast cancer patients. Together, these studies highlight p38 MAPK, HBP1, and RB as important components for a premature-senescence pathway with possible clinical relevance to breast cancer.

* Corresponding author. Mailing address: Tufts University School of Medicine, Dept. of Biochemistry (Jaharis 614), 136 Harrison Ave., Boston, MA 02111. Phone: (617) 636-6850. Fax: (617) 636-2409. E-mail: amy.yee{at}tufts.edu.

{triangledown} Published ahead of print on 11 September 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2006, p. 8252-8266, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00604-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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