Immortalization of primary human keratinocytes by the helix-loop-helix protein, Id-1
Immortalization of primary human keratinocytes by the helix-loop-helix protein, Id-1
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DOI：
10.1073/pnas.96.17.9637
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发表时间：
1999-08-17
影响因子：
11.1
通讯作者：
M端nger, K
中科院分区：
文献类型：
--
作者：
Alani, RM;Hasskarl, J;M端nger, K
碱性螺旋-环-螺旋（bHLH）DNA结合蛋白已被证明在多种细胞谱系内调节组织特异性转录。螺旋-环-螺旋蛋白的Id家族不具有基本的DNA结合结构域，并且作为bHLH蛋白的负调节物起作用。Id蛋白在多种细胞类型内的过表达已显示抑制它们在适当条件下分化的能力。我们证明，异位表达的Id-1导致端粒酶活性的激活和永生化的原代人角质形成细胞。这些永生化细胞的分化能力降低，并激活视网膜母细胞瘤蛋白的磷酸化。此外，这些细胞获得受损的p53介导的DNA损伤反应作为永生化的晚期事件，我们得出结论，bHLH蛋白在调节正常角质形成细胞的生长和分化中起着关键作用，这可以被Id-1通过激活端粒酶活性和失活视网膜母细胞瘤蛋白的永生化功能破坏。
Basic helix-loop-helix (bHLH) DNA-binding proteins have been demonstrated to regulate tissue-specific transcription within multiple cell lineages. The Id family of helix-loop-helix proteins does not possess a basic DNA-binding domain and functions as a negative regulator of bHLH proteins. Overexpression of Id proteins within a variety of cell types has been shown to inhibit their ability to differentiate under appropriate conditions. We demonstrate that ectopic expression of Id-1 leads to activation of telomerase activity and immortalization of primary human keratinocytes. These immortalized cells have a decreased capacity to differentiate as well as activate phosphorylation of the retinoblastoma protein. Additionally, these cells acquire an impaired p53-mediated DNA-damage response as a late event in immortalization, We conclude that bHLH proteins play a pivotal role in regulating normal keratinocyte growth and differentiation, which can be disrupted by the immortalizing functions of Id-1 through activation of telomerase activity and inactivation of the retinoblastoma protein.