Isoform- and dose-sensitive feedback interactions between paired box 6 gene and delta-catenin in cell differentiation and death.
Isoform- and dose-sensitive feedback interactions between paired box 6 gene and delta-catenin in cell differentiation and death.
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DOI：
10.1016/j.yexcr.2010.01.006
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发表时间：
2010-04-01
影响因子：
3.7
通讯作者：
Lu Q
中科院分区：
文献类型：
--
作者：
Zhang J;Lu JP;Suter DM;Krause KH;Fini ME;Chen B;Lu Q
Pax6 是在干细胞和祖细胞中表达的果蝇配对盒基因家族成员的哺乳动物同源物，位于控制细胞命运和形态发生的遗传层次的顶部。虽然 Pax6 激活可导致有丝分裂停滞、过早神经发生和细胞凋亡，但潜在的分子机制尚未得到解决。在这里，我们报告 Pax6(+5a) 或 Pax6(−5a) 足以促进，而它们的敲低降低了 δ-连环蛋白 (CTNND2) 的表达，δ-连环蛋白是犰狳/β-连环蛋白超家族的神经特异性成员。 Pax6(+5a) 对 δ-连环蛋白的影响比 Pax6(−5a) 更强。诱导型 Pax6(+5a) 表达证明了 δ-连环蛋白表达和细胞命运的双相和剂量依赖性调节。 Pax6(+5a)的适度上调促进δ-连环蛋白表达并诱导神经突样细胞突起，但Pax6(+5a)表达的增加逆转了这些过程。此外，Pax6(+5a)的持续高表达引发细胞凋亡，这通过磷酸-Bad、Bcl-2、生存素和前天冬酶的减少以及Bax和裂解聚(ADP-核糖)聚合酶的增加来确定。重要的是，通过异位表达重新引入δ-连环蛋白引起了对Pax6(+5a)表达的反馈抑制并减少了Pax6(+5a)诱导的细胞凋亡。因此，δ-连环蛋白的表达不仅受Pax6控制，而且还为它们的功能相互作用提供反馈抑制机制，对细胞形态发生、细胞凋亡和癌症具有重要意义。
Pax6, a mammalian homolog of the Drosophila paired box gene family member expressed in stem and progenitor cells, resides at the top of the genetic hierarchy in controlling cell fates and morphogenesis. While Pax6 activation can lead to mitotic arrest, premature neurogenesis, and apoptosis, the underlying molecular mechanisms have not been resolved. Here we report that either Pax6(+5a) or Pax6(−5a) was sufficient to promote, whereas their knockdown reduced the expression of δ-catenin (CTNND2), a neural specific member of the armadillo/β-catenin superfamily. Pax6(+5a) elicited stronger effects on δ-catenin than Pax6(−5a). Inducible Pax6(+5a) expression demonstrated a biphasic and dose-dependent regulation of δ-catenin expression and cell fates. A moderate upregulation of Pax6(+5a) promoted δ-catenin expression and induced neurite-like cellular protrusions, but increasing expression of Pax6(+5a) reversed these processes. Furthermore, sustained high expression of Pax6(+5a) triggered apoptosis as determined by the reduction of phospho-Bad, Bcl-2, survivin and procaspases, as well as the increases in Bax and cleaved poly(ADP-ribose) polymerase. Importantly, re-introducing δ-catenin by ectopic expression elicited a feedback suppression on Pax6(+5a) expression and reduced Pax6(+5a) induced apoptosis. Therefore, δ-catenin expression is not only controlled by Pax6, but it also provides a feedback suppression mechanism for their functional interactions with important implications in cellular morphogenesis, apoptosis, and cancer.
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