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首页> 外文期刊>Molecular and Cellular Biology >HES-1 Repression of Differentiation and Proliferation in PC12 Cells: Role for the Helix 3-Helix 4 Domain in Transcription Repression
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HES-1 Repression of Differentiation and Proliferation in PC12 Cells: Role for the Helix 3-Helix 4 Domain in Transcription Repression

机译：HES-1抑制PC12细胞分化和增殖：螺旋3螺旋4域在转录抑制中的作用。

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HES-1 is a Hairy-related basic helix-loop-helix protein with three evolutionarily conserved regions known to define its function as a transcription repressor. The basic region, helix-loop-helix domain, and WRPW motif have been characterized for their molecular function in DNA binding, dimer formation, and corepressor recruitment, respectively. In contrast, the function conferred by a fourth conserved region, the helix 3-helix 4 (H-3/4) domain, is not known. To better understand H-3/4 domain function, we expressed HES-1 variants under tetracycline-inducible control in PC12 cells. As expected, the induced expression of moderate levels of wild-type HES-1 in PC12 cells strongly inhibited nerve growth factor-induced differentiation. This repression was dependent on the H-3/4 domain. Unexpectedly, expression of HES-1 also arrested cell growth, an effect that could be reversed upon down regulation of HES-1. Concomitant with growth arrest, there was a strong reduction in bromodeoxyuridine incorporation and PCNA protein levels, although not in cyclin D1 expression. Expression of a HES-1 protein carrying the H-3/4 domain, but not the WRPW domain, still partially inhibited both proliferation and differentiation. Transcription assays in PC12 cells directly demonstrated that the H-3/4 domain can mediate DNA-binding-dependent transcription repression, even in the absence of corepressor recruitment by the WRPW motif. HES-1 expression strongly repressed transcription of the p21 cip1promoter, a cyclin–cyclin-dependent kinase inhibitor up regulated during NGF-induced differentiation, and the H-3/4 domain is necessary for this repression. Thus, the H-3/4 domain of HES-1 contributes to transcription repression independently of WRPW function, inhibits neurite formation, and facilitates two distinct and previously uncharacterized roles for HES-1: the inhibition of cell proliferation and the direct transcriptional repression of the NGF-induced gene,p21.
机译：HES-1是毛发相关的基本螺旋-环-螺旋蛋白，具有三个进化保守区域，已知其定义其作为转录阻遏物的功能。基本区域，螺旋-环-螺旋结构域和WRPW主题已被分别表征其在DNA结合，二聚体形成和corepressor募集中的分子功能。相反，未知的是第四个保守区，即螺旋3螺旋4（H-3 / 4）域所赋予的功能。为了更好地了解H-3 / 4结构域功能，我们在PC12细胞中在四环素诱导控制下表达了HES-1变体。不出所料，PC12细胞中中等水平的野生型HES-1的诱导表达强烈抑制了神经生长因子诱导的分化。这种抑制取决于H-3 / 4域。出乎意料的是，HES-1的表达也阻止了细胞的生长，这种作用在下调HES-1时可以逆转。伴随着生长停滞，尽管没有细胞周期蛋白D1的表达，但溴脱氧尿苷掺入和PCNA蛋白水平却大大降低。带有H-3 / 4结构域而不是WRPW结构域的HES-1蛋白的表达仍然部分抑制增殖和分化。在PC12细胞中进行的转录检测直接证明，即使在没有WRPW基序募集共募因子的情况下，H-3 / 4结构域也可以介导DNA结合依赖性转录抑制。 HES-1表达强烈抑制 p21 cip1 启动子的转录，这是一种细胞周期蛋白依赖性细胞周期蛋白依赖性激酶抑制剂，在NGF诱导的分化过程中被上调，而H-3 / 4域对于这种压制是必要的。因此，HES-1的H-3 / 4结构域与WRPW功能无关，有助于转录抑制，抑制神经突形成，并促进HES-1的两个不同的和以前未表征的作用：抑制细胞增殖和直接转录抑制。 NGF诱导的基因， p21 。

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