beta-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epithelia.
beta-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epithelia.
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DOI：
10.1016/j.yexcr.2008.10.019
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发表时间：
2009-01-01
影响因子：
3.7
通讯作者：
Umar S
中科院分区：
文献类型：
--
作者：
Sellin JH;Wang Y;Singh P;Umar S
利用罗氏柠檬酸杆菌诱导的小鼠传递性结肠增生模型，我们为体内β-连环蛋白/蛋白C/肌动蛋白Iε的变化导致增殖的进展和/或消退提供了机制基础。对于CR诱导的TMCH，在感染后6-27天，隐窝长度显著增加，随后在第34天急剧下降。β-Cat45/总β-Catenin在感染后第1天升高，在隐窝长度改变之前，并持续27天，到第34天下降。重要的是，细胞CKIε和β-连环蛋白免疫共沉淀，并在增殖/退化期表现出显著的平行动力学变化。β-连环蛋白，在Ser33，37和Thr41处磷酸化(β-Cat33，37/41)，低至第12天，随后逐渐上升，至第27天，至第34天下降。GSK-3β在第6-12天表现出明显的Ser9磷酸化/失活，在第27-34天部分恢复。野生型(Wt)APC(P312)水平在第6天升高，在第12-15天之间瞬时蛋白降解/截断为p130形式；第19天重新出现p312，第34天恢复到基线水平。β-Cat45/β-Catenin的核聚集和乙酰化(Ac-β-Catlys49)在β-Cat45/β-Catenin免疫共沉淀和免疫组织化学定位于β-Cat41/45阳性区域，导致Cyclin D1表达升高，在TMCH的高增殖期，而不是退化期。CKIε介导的β-Cat45的磷酸化，导致β-Cat45的稳定/核转位，可能是维持6-27天细胞增殖的关键。在从第27-34天开始的回归阶段，逆转葛兰素史克-3β的磷酸化和蛋白原结合蛋白的变化可能同样重要。
Utilizing the Citrobacter rodentium (CR)-induced transmissible murine colonic hyperplasia (TMCH) model, we provide mechanistic basis of changes in β-catenin/APC/CKIε leading to progression and/or regression of hyperplasia in vivo. In response to CR-induced TMCH, crypt lengths increased significantly between Days6–27 post-infection, followed by a steep decline by Day34. β-Cat45/total β-catenin were elevated on Day1 post-infection, preceding changes in crypt length, and persisted for 27days before declining by Day34. Importantly, cellular CKIε and β-catenin co-immunoprecipitated and exhibited remarkable parallel changes in kinetics during hyperplasia/regression phases. β-catenin, phosphorylated at Ser33,37 and Thr41 (β-cat33,37/41), was low till Day12, followed by gradual increase until Day27 before declining by Day34. GSK-3β exhibited significant Ser9-phosphorylation/inactivation at Days6–12 with partial recovery at Days27–34. Wild type (wt) APC (p312) levels increased at Day6 with transient proteolysis/truncation to p130 form between Days12–15; p312 reappeared by Day19 and returned to baseline by Day34. The kinetics of β-Cat45/β-catenin nuclear accumulation and acetylation (Ac-β-CatLys49) from Days6–27, followed by loss of phosphorylation/acetylation by Day34 was almost identical; Tcf-4 co-immunoprecipitated with β-Cat45/β-catenin and localized immunohistochemically to β-Cat41/45-positive regions leading to elevated cyclin D1 expression, during the hyperproliferative, but not regression phases of TMCH. CKIε mediated phosphorylation of β-Cat45, resulting in stabilization/nuclear translocation of β-Cat45 may be critical for maintaining proliferation at Days6–27. Reversal of GSK-3β phosphorylation and APC changes may be equally critical during the regression phase from Days27–34.
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