Role of the translational repressor 4E-BP1 in the regulation of p21^Waf1/Cip1 expression by retinoids

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• 作者：Padma Kannan-Thulasiraman ; Blazej Dolniak ; Surinder Kaur ; Antonella Sassano ; Dhananjaya V. Kalvakolanu ; Nissim Hay ; Leonidas C. Platanias
• 关键词：Retinoids ; Signaling ; mRNA translation
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2008
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：18 April 2008
• 卷：368
• 期：4
• 页码：983-989
• 文件大小：422 K

摘要

The mechanisms by which retinoids regulate initiation of mRNA translation for proteins that mediate their biological effects are not known. We have previously shown that all-trans-retinoic acid (ATRA) induces mTOR-mediated activation of the p70 S6 kinase, suggesting the existence of a mechanism by which retinoids may regulate mRNA translation. We now demonstrate that treatment of acute promyelocytic leukemia (APL)-derived NB4 cells with ATRA results in dissociation of the translational repressor 4E-BP1 from the eukaryotic initiation factor eIF4E, and subsequent formation of eIF4G-eIF4E complexes. We also show that siRNA-mediated inhibition of 4E-BP1 expression enhances ATRA-dependent upregulation of p21^Waf1/Cip1, a protein that plays a key role in the induction of retinoid-dependent responses. Our data also establish that ATRA- or cis-RA-dependent p21^Waf1/Cip1 protein expression is enhanced in mouse embryonic fibroblasts with targeted disruption of the 4e-bp1 gene, in the absence of any effects on the transcriptional regulation of the p21^Waf1/Cip1 gene. Moreover, generation of ATRA- or cis-retinoic acid (cis-RA)-antiproliferative responses is enhanced in 4E-BP1 knockout cells. Altogether, these findings strongly suggest a key regulatory role for the translational repressor 4E-BP1 in the generation of retinoid-dependent functional responses.