Interaction of BAG-1 with retinoic acid receptor and its inhibition of retinoic acid-induced apoptosis in cancer cells.
BAG-1 (also known as RAP46) is an anti-apoptotic protein, which has been shown previously to interact with a number of nuclear hormone receptors, including receptors for glucocorticoid, estrogen, and thyroid hormone. We show here that BAG-1 also interacts with retinoic acid receptor (RAR). Gel retardation assays demonstrated that in vitro translated BAG-1 protein could effectively inhibit the binding of RAR but not retinoid X receptor (RXR) to a number of retinoic acid (RA) response elements (RAREs). A glutathione S-transferase-BAG-1 fusion protein also specifically bound RAR but not RXR. Interaction of BAG-1 and RAR could also be demonstrated by yeast two-hybrid assays. In transient transfection assays, co-transfection of BAG-1 expression plasmid inhibited the transactivation activity of RAR/RXR heterodimers but not RXR/RXR homodimers. When stably expressed in breast cancer cell lines, BAG-1 inhibited binding of RAR/RXR heterodimer to a number of RAREs and suppressed RA-induced growth inhibition and apoptosis. In addition, RA-induced suppression of Bcl-2 expression was abrogated by overexpression of BAG-1. These results demonstrate that BAG-1 can regulate retinoid activities through its interaction with RAR and suggest that elevated levels of BAG-1 protein could potentially contribute to retinoid resistance in cancer cells.
Liu
R
R
The Burnham Institute, Cancer Research Center, La Jolla, California 92037, USA.
Takayama
S
S
Zheng
Y
Y
Froesch
B
B
Chen
G Q
GQ
Zhang
X
X
Reed
J C
JC
Zhang
X K
XK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D000882:Haplorhini; D006801:Humans; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D014212:Tretinoin