Kannan-Thulasiraman Padma, Dolniak Blazej, Kaur Surinder, Sassano Antonella, Kalvakolanu Dhananjaya V, Hay Nissim, Platanias Leonidas C
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School and Jesse Brown VA Medical Center, 303 East Superior, Chicago, IL, USA.
Biochem Biophys Res Commun. 2008 Apr 18;368(4):983-9. doi: 10.1016/j.bbrc.2008.02.028. Epub 2008 Feb 15.
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.
类视黄醇调节介导其生物学效应的蛋白质的mRNA翻译起始的机制尚不清楚。我们之前已经表明，全反式维甲酸（ATRA）可诱导mTOR介导的p70 S6激酶激活，这表明存在一种类视黄醇可能调节mRNA翻译的机制。我们现在证明，用ATRA处理急性早幼粒细胞白血病（APL）来源的NB4细胞会导致翻译抑制因子4E-BP1与真核起始因子eIF4E解离，并随后形成eIF4G-eIF4E复合物。我们还表明，siRNA介导的4E-BP1表达抑制增强了p21（Waf1/Cip1）的ATRA依赖性上调，p21（Waf1/Cip1）是一种在类视黄醇依赖性反应诱导中起关键作用的蛋白质。我们的数据还证实，在4e-bp1基因靶向破坏的小鼠胚胎成纤维细胞中，ATRA或顺式维甲酸（cis-RA）依赖性的p21（Waf1/Cip1）蛋白表达增强，而对p21（Waf1/Cip1）基因的转录调控没有任何影响。此外，在4E-BP1基因敲除细胞中，ATRA或顺式维甲酸（cis-RA）的抗增殖反应增强。总之，这些发现强烈表明翻译抑制因子4E-BP1在类视黄醇依赖性功能反应的产生中起关键调节作用。
