MCB
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ren, M.
Right arrow Articles by Sacchi, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ren, M.
Right arrow Articles by Sacchi, N.
Molecular and Cellular Biology, December 2005, p. 10591-10603, Vol. 25, No. 23
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.23.10591-10603.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Impaired Retinoic Acid (RA) Signal Leads to RARß2 Epigenetic Silencing and RA Resistance

MingQiang Ren, Silvia Pozzi, Gaia Bistulfi, Giulia Somenzi, Stefano Rossetti, and Nicoletta Sacchi*

Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263

Received 25 May 2005/ Returned for modification 13 July 2005/ Accepted 16 September 2005

Resistance to the growth-inhibitory action of retinoic acid (RA), the bioactive derivative of vitamin A, is common in human tumors. One form of RA resistance has been associated with silencing and hypermethylation of the retinoic acid receptor ß2 gene (RARß2), an RA-regulated tumor suppressor gene. The presence of an epigenetically silent RARß2 correlates with lack of the RA receptor {alpha} (RAR{alpha}). Normally, RAR{alpha} regulates RARß2 transcription by mediating dynamic changes of RARß2 chromatin in the presence and absence of RA. Here we show that interfering with RA signal through RAR{alpha} (which was achieved by use of a dominant-negative RAR{alpha}, by downregulation of RAR{alpha} by RNA interference, and by use of RAR{alpha} antagonists) induces an exacerbation of the repressed chromatin status of RARß2 and leads to RARß2 transcriptional silencing. Further, we demonstrate that RARß2 silencing causes resistance to the growth-inhibitory effect of RA. Apparently, RARß2 silencing can also occur in the absence of DNA methylation. Conversely, we demonstrate that restoration of RA signal at a silent RARß2 through RAR{alpha} leads to RARß2 reactivation. This report provides proof of principle that RARß2 silencing and RA resistance are consequent to an impaired integration of RA signal at RARß2 chromatin.


* Corresponding author. Mailing address: Roswell Park Cancer Institute, Elm & Carlton Streets, C&V Bldg., RM 226, Buffalo, NY 14263. Phone: (716) 845-1053. Fax: (716) 845-1741. E-mail: nicoletta.sacchi{at}roswellpark.org.


Molecular and Cellular Biology, December 2005, p. 10591-10603, Vol. 25, No. 23
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.23.10591-10603.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.




This article has been cited by other articles:




Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
J. Bacteriol. J. Virol. Eukaryot. Cell
Microbiol. Mol. Biol. Rev. Clin. Vaccine Immunol. All ASM Journals

Copyright © 2005 by the American Society for Microbiology. All rights reserved.