Wu, Siqin
- Department of Plant Biology, Swedish University of Agricultural Sciences
Research article2009Peer reviewed
TGF-beta enforces senescence in Myc-transformed hematopoietic tumor cells through induction of Mad1 and repression of Myc activity
Wu, Siqin; Hultquist, Anne; Hydbring, Per; Cetinkaya, Cihan; Öberg, Fredrik; Larsson, Lars-Gunnar
Abstract
Inhibition of tumor growth factor (TGF)-beta-mediated cell cycle exit is considered an important tumorigenic function of Myc oncoproteins. Here we found that TGF-beta 1 enforced G, cell cycle arrest and cellular senescence in human U-937 myeloid tumor cells ectopically expressing v-Myc, which contains a stabilizing mutation frequently found in lymphomas. This correlated with induced expression of the Myc antagonist Mad1, resulting in replacement of Myc for Mad1 at target promoters, reduced histone acetylation and strong repression of Myc-driven transcription. The latter was partially reversed by histone deacetylase (HDAC) inhibitors, consistent with involvement of Mad1. Importantly, knockdown of MAD1 expression prevented TGF-beta 1-induced senescence, underscoring that Mad1 is a crucial component of this process. Enforced Mad1 expression sensitized U-937-myc cells to TGF-beta and restored phorbol ester-induced cell cycle exit, but Could not alone induce G, arrest, suggesting that Mad1 is required but not sufficient for cellular senescence. Our results thus demonstrate that TGF-beta can override Myc activity despite a stabilizing cancer Mutation and induce senescence in myeloid tumor cells, at least in part by induction of Mad1. TGF-beta-induced senescence, or signals mimicking this pathway, could therefore potentially be explored as a therapeutic principle for treating hematopoietic and other tumors with deregulated MYC expression. (C) 2009 Elsevier Inc. All rights reserved.
Keywords
Myc; Mad; TGF-beta; Senescence; Cell cycle; Cancer
Published in
Experimental Cell Research
2009, volume: 315, number: 18, pages: 3099-3111
Publisher: ELSEVIER INC
SLU Authors
Hydbring, Per
- Department of Plant Biology, Swedish University of Agricultural Sciences
- Karolinska Institute
- Department of Plant Biology, Swedish University of Agricultural Sciences
Cetinkaya, Cihan
- Department of Plant Biology, Swedish University of Agricultural Sciences
- Uppsala University
- Department of Plant Biology, Swedish University of Agricultural Sciences
Larsson, Lars-Gunnar
- Department of Plant Biology, Swedish University of Agricultural Sciences
- Karolinska Institute
- Department of Plant Biology, Swedish University of Agricultural Sciences
UKÄ Subject classification
Food Science
Animal and Dairy Science
Veterinary Science
Publication identifier
- DOI: https://doi.org/10.1016/j.yexcr.2009.09.009
Permanent link to this page (URI)
https://res.slu.se/id/publ/61215