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Role of the PKA‐Regulated Transcription Factor CREB in Development and Tumorigenesis of Endocrine Tissues
Author(s) -
ROSENBERG D.,
GROUSSIN L.,
JULLIAN E.,
PERLEMOINE K.,
BERTAGNA X.,
BERTHERAT J.
Publication year - 2002
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2002.tb04327.x
Subject(s) - creb , creb1 , transcription factor , biology , cyclic amp response element binding protein , response element , activating transcription factor 2 , endocrinology , medicine , cancer research , promoter , microbiology and biotechnology , gene expression , gene , genetics
A bstract : 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 Gαs 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 GαS 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 CREMτ is observed in the human adrenocortical cancer cell line H295R. Similar alterations are found 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.