Turano Mimmo, Napolitano Giuliana, Dulac Cyprien, Majello Barbara, Bensaude Olivier, Lania Luigi
Department of Structural and Functional Biology, University of Naples Federico II, Naples, Italy.
J Cell Physiol. 2006 Mar;206(3):603-10. doi: 10.1002/jcp.20502.
The HEXIM1 protein, in association with 7SK snRNA, binds and inhibits the kinase activity of P-TEFb (CDK9/cyclin T). P-TEFb activity is crucial for efficient transcription elongation of viral and cellular genes. HEXIM1 was originally isolated as a protein up-regulated by hexamethylene bisacetamide (HMBA), a prototypical inducer of differentiation. To determine the causative role of HEXIM1 during cell differentiation we analyzed the biochemical and functional consequences of HEXIM1 protein levels in several in vitro differentiation systems. We found that HEXIM1 mRNA and protein levels are up-regulated during differentiation of murine erythroleukemia cells upon treatment with HMBA or DMSO. Stimulation of HEXIM1 is not restricted to hematopoietic cells, as induction of phenotypic differentiation of neuroblastoma cells by retinoic acid results in up-regulation of HEXIM1. Moreover, ectopic expression of HEXIM1 causes growth inhibition and promotes neuronal differentiation. These findings highlight a crucial role of HEXIM1 protein during cell differentiation.
HEXIM1蛋白与7SK小核仁RNA结合，抑制P-TEFb（细胞周期蛋白依赖性激酶9/细胞周期蛋白T）的激酶活性。P-TEFb活性对于病毒和细胞基因的高效转录延伸至关重要。HEXIM1最初作为一种被六亚甲基双乙酰胺（HMBA，一种典型的分化诱导剂）上调的蛋白质被分离出来。为了确定HEXIM1在细胞分化过程中的因果作用，我们分析了几种体外分化系统中HEXIM1蛋白水平的生化和功能后果。我们发现，在用HMBA或二甲基亚砜处理后，小鼠红白血病细胞分化过程中HEXIM1 mRNA和蛋白水平上调。HEXIM1的刺激并不局限于造血细胞，因为视黄酸诱导神经母细胞瘤细胞的表型分化会导致HEXIM1上调。此外，HEXIM1的异位表达会导致生长抑制并促进神经元分化。这些发现突出了HEXIM1蛋白在细胞分化过程中的关键作用。
