Open AccessThe HBP1 Transcriptional Repressor Participates in RAS-Induced Premature Senescence
Author(s) -
Xiaowei Zhang,
Jiyoung Kim,
Robin Ruthazer,
Michael A. McDevitt,
David E. Wazer,
K. Eric Paulson,
Amy S. Yee
Publication year - 2006
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00604-06
Subject(s) - biology , senescence , repressor , mapk/erk pathway , microbiology and biotechnology , transcriptional regulation , p38 mitogen activated protein kinases , cancer research , gene knockdown , signal transduction , transcription factor , genetics , cell culture , gene
Oncogene-mediatedpremature senescence has emerged as a potential tumor-suppressivemechanism in early cancer transitions. Previous work shows that RAS andp38 MAPK participate in premature senescence, but transcriptionaleffectors have not been identified. Here, we demonstrate that the HBP1transcriptional repressor participates in RAS- and p38 MAPK-inducedpremature senescence. In cell lines, we had previously isolated HBP1 asa retinoblastoma (RB) target but have determined that it functions as aproliferation regulator by inhibiting oncogenic pathways as atranscriptional repressor. In primary cells, the resultsindicate that HBP1 is a necessary component of premature senescence byRAS and p38 MAPK. Similarly, a knockdown of WIP1 (a p38 MAPKphosphatase) induced premature senescence that also required HBP1.Furthermore, HBP1 requires regulation by RB, in which fewtranscriptional regulators for premature senescence have been shown.Together, the data suggest a model in which RAS and p38 MAPK signalingengage HBP1 and RB to trigger premature senescence. As an initial steptoward clinical relevance, a bioinformatics approach shows that therelative expression levels of HBP1 and WIP1 correlated with decreasedrelapse-free survival in breast cancer patients. Together, thesestudies highlight p38 MAPK, HBP1, and RB as important components for apremature-senescence pathway with possible clinical relevance to breastcancer.