CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells
CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells
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DOI：
10.1158/0008-5472.can-11-3320
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发表时间：
2012-03-15
期刊：
影响因子：
11.2
通讯作者：
Santoro, Massimo
中科院分区：
文献类型：
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作者：
De Falco, Valentina;Tamburrino, Anna;Santoro, Massimo
CD 44是癌症干细胞样细胞和上皮-间充质转化的标志物，在许多癌症类型中过表达，包括甲状腺癌。在细胞外和膜内结构域，CD 44经历连续的金属蛋白酶和γ-分泌酶介导的蛋白水解切割，释放细胞内蛋白片段CD 44-ICD，其易位到细胞核并激活基因转录。在这里，我们表明，CD 14-ICD结合到转录因子CREB，增加S133磷酸化和CREB介导的基因转录。CD 44-ICD增强CREB向细胞周期蛋白D1启动子的募集，促进细胞周期蛋白D1的转录和细胞增殖。携带激活的RET/PTC、RAS或BRAE癌基因的甲状腺癌细胞表现出CD 44裂解和CD 14-ICD蓄积。RET/PTC、BRAE、金属蛋白酶或γ-分泌酶的化学阻断各自足以钝化CD 44加工。此外，甲状腺癌细胞增殖被RNA干扰介导的CD 44敲低或γ-分泌酶抑制所阻碍，并且过继性CD 44-ICD过表达挽救了细胞增殖。总之，这些发现揭示了维持癌细胞增殖所需的CD 44-CREB信号通路，可能为甲状腺癌的治疗干预提供新的分子靶点。Cancer Res; 72（6）; 1449-58. (C)2012年AACR。
CD44 is a marker of cancer stem-like cells and epithelial-mesenchymal transition that is overexpressed in many cancer types, including thyroid carcinoma. At extracellular and intramembranous domains, CD44 undergoes sequential metalloprotease- and gamma-secretase-mediated proteolytic cleavage, releasing the intracellular protein fragment CD44-ICD, which translocates to the nucleus and activates gene transcription. Here, we show that CD14-ICD binds to the transcription factor CREB, increasing S133 phosphorylation and CREB-mediated gene transcription. CD44-ICD enhanced CREB recruitment to the cyclin D1 promoter, promoting cyclin D1 transcription and cell proliferation. Thyroid carcinoma cells harboring activated RET/PTC, RAS, or BRAE oncogenes exhibited CD44 cleavage and CD14-ICD accumulation. Chemical blockade of RET/PTC, BRAE, metalloprotease, or gamma-secretase were each sufficient to blunt CD44 processing. Furthermore, thyroid cancer cell proliferation was obstructed by RNA interference-mediated knockdown of CD44 or inhibition of gamma-secretase and adoptive CD44-ICD overexpression rescued cell proliferation. Together, these findings reveal a CD44-CREB signaling pathway that is needed to sustain cancer cell proliferation, potentially offering new molecular targets for therapeutic intervention in thyroid carcinoma. Cancer Res; 72(6); 1449-58. (C) 2012 AACR.