Role of the PKA-regulated transcription factor CREB in development and tumorigenesis of endocrine tissues
Role of the PKA-regulated transcription factor CREB in development and tumorigenesis of endocrine tissues
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DOI：
10.1111/j.1749-6632.2002.tb04327.x
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发表时间：
2002-01-01
期刊：
影响因子：
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通讯作者：
Bertherat, J
中科院分区：
文献类型：
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作者：
Rosenberg, D;Groussin, L;Bertherat, J
cAMP通路在内分泌组织的发育中起主要作用，并且该通路的关键组分（G蛋白、受体、PKA等）的各种分子缺陷也起主要作用。已经在内分泌肿瘤中观察到。普遍存在的转录因子CREB（cAMP-反应元件结合蛋白）与cAMP反应元件（CRE）结合，并在通过PKA在Ser（133）上磷酸化后刺激转录。CREB转录因子家族包含三个成员：CREB、CREM和ATF-1。CREB显性负突变体在转基因小鼠中的靶向表达导致生长激素细胞或甲状腺发育不全。生长激素分泌腺瘤是一种良性分泌性肿瘤，约40%的病例表达激活的突变型Galphas蛋白（Gsp）。在生长激素分泌腺瘤中，CREB总是表达并且经常高度磷酸化。CREM亚型ICER受cAMP刺激，其表达在携带Gsp的肿瘤中增加。在垂体促生长细胞中转染后，Gs蛋白（Gsp）的激活突变和野生型GalphaS的过表达以Ser（133）特异性依赖的方式通过CREB刺激各种含CREB启动子的转录。肾上腺皮质（AdCx）维持和类固醇生成需要ACTH激活cAMP通路。CREB在正常AdCx中表达。在人肾上腺皮质癌细胞系H295 R中观察到CRE结合蛋白的改变，伴随CREB表达的丧失和CREMtau的代偿性过表达。在人类恶性肾上腺皮质肿瘤的蛋白质水平上也发现了类似的改变.总之，CREB家族转录因子在内分泌组织的发育、分化和增殖中起着重要作用。在内分泌肿瘤中可以观察到CREB家族转录因子的各种改变。
The cAMP pathway plays a major role in the development of endocrine tissues and various molecular defects of key components of this pathway (G protein, receptors, PKA, etc.) have been observed in endocrine tumors. The ubiquitous transcription factor CREB (cAMP-response element binding protein) binds to the cAMP response element (CRE) and stimulates transcription after phosphorylation on Ser(133) by PKA. The CREB family of transcription factors contains three members: CREB, CREM, and ATF-1. Targeted expression of dominant-negative mutants of CREB in transgenic mice leads to somatotrophs or thyroid hypoplasia. GH-secreting adenomas are benign secreting tumors expressing an activated mutant Galphas protein (Gsp) in about 40% of cases. In GH-secreting adenomas CREB is always expressed and often highly phosphorylated. The CREM isoform ICER is stimulated by cAMP, and its expression is increased in Gsp-harboring tumors. After transfection in pituitary somatotroph cells, activating mutations of Gs protein (Gsp) and overexpression of wild-type GalphaS stimulate transcription of various CRE-containing promoters via CREB in a Ser(133)-specific-dependent manner. Activation of the cAMP pathway by ACTH is required for adrenal cortex (AdCx) maintenance and steroidogenesis. CREB is expressed in normal AdCx. Alterations of CRE binding proteins with loss of CREB expression and compensatory overexpression of CREMtau is observed in the human adrenocortical cancer cell line H295R. Similar alterations are Fund at the protein level in human malignant adrenocortical tumors. In conclusion, the CREB family of transcription factors plays an important role in the development, differentiation, and proliferation of endocrine tissues. Various alterations of the CREB family of transciption factors can be observed in endocrine tumors.