Peroxisome proliferator-activated receptor gamma and transforming growth factor-beta pathways inhibit intestinal epithelial cell growth by regulating levels of TSC-22.
Peroxisome proliferator-activated receptor gamma and transforming growth factor-beta pathways inhibit intestinal epithelial cell growth by regulating levels of TSC-22.
复制标题
DOI：
--
复制
发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Rajnish A. Gupta;P. Sarraf;J. Brockman;S. Shappell;L. Raftery;T. Willson;R. Dubois
中科院分区：
文献类型：
--
作者：
Rajnish A. Gupta;P. Sarraf;J. Brockman;S. Shappell;L. Raftery;T. Willson;R. Dubois
过氧化物酶体增殖物激活受体γ（PPARgamma）和转化生长因子β（TGF-β）是上皮细胞生物学的关键调节因子。然而，这两种途径诱导生长抑制和分化的分子机制还不完全清楚。我们已经确定了转化生长因子模拟克隆-22（TSC-22）作为肠上皮细胞中两种途径的靶基因。TSC-22是含有具有阻遏物活性的转录因子的亮氨酸拉链家族的成员。尽管对TSC-22在哺乳动物中的功能知之甚少，但果蝇中TSC-22的同源物bunched在果蝇发育中起着至关重要的作用。PPARgamma诱导TSC-22的能力不依赖于完整的TGF-β 1信号通路，并且对γ亚型具有特异性。定位研究表明，TSC-22 mRNA是丰富的有丝分裂后的正常人结肠上皮隔室。与载体转染的细胞相比，野生型TSC-22转染的细胞表现出降低的生长速率和增加的p21水平。此外，转染显性负性TSC-22，其中两个阻遏物结构域被删除，能够逆转由激活PPARgamma或TGF-β途径引起的p21诱导和生长抑制。这些结果将TSC-22作为肠上皮细胞分化期间PPARgamma和TGF-β信号传导的重要下游组分。
Peroxisome proliferator-activated receptor gamma (PPARgamma) and transforming growth factor-beta (TGF-beta) are key regulators of epithelial cell biology. However, the molecular mechanisms by which either pathway induces growth inhibition and differentiation are incompletely understood. We have identified transforming growth factor-simulated clone-22 (TSC-22) as a target gene of both pathways in intestinal epithelial cells. TSC-22 is member of a family of leucine zipper containing transcription factors with repressor activity. Although little is known regarding its function in mammals, the Drosophila homolog of TSC-22, bunched, plays an essential role in fly development. The ability of PPARgamma to induce TSC-22 was not dependent on an intact TGF-beta1 signaling pathway and was specific for the gamma isoform. Localization studies revealed that TSC-22 mRNA is enriched in the postmitotic epithelial compartment of the normal human colon. Cells transfected with wild-type TSC-22 exhibited reduced growth rates and increased levels of p21 compared with vector-transfected cells. Furthermore, transfection with a dominant negative TSC-22 in which both repressor domains were deleted was able to reverse the p21 induction and growth inhibition caused by activation of either the PPARgamma or TGF-beta pathways. These results place TSC-22 as an important downstream component of PPARgamma and TGF-beta signaling during intestinal epithelial cell differentiation.