CREM, a master-switch of the transcriptional cascade in male germ cells.
In eukaryotes, transcriptional regulation upon stimulation of the adenylyl cyclase signalling pathway is mediated by a family of cAMP-responsive nuclear factors. The CREB and CREM transcription factors are activated by phosphorylation of a key serine residue by kinase stimulated by cyclic AMP, calcium, growth factors and stress signals. Phosphorylation allows recruitment of CBP (CREB Binding Protein), a large co-activator that contacts the general transcriptional machinery. The CREM gene plays a key physiological and developmental role within the hypothalamic-pituitary-gonadal axis. CREM is highly expressed in postmeiotic cells upon a striking developmental switch regulated by the pituitary hormone FSH. CREM-mutant mice generated by homologous recombination reveal that spermatogenesis stops at the first step of spermiogenesis. Late spermatids are completely absent while there is a significant increase in apoptotic germ cells. Mutant male mice completely lack spermatozoa, a phenotype reminiscent of cases of human infertility. Interestingly, in male germ cells, CREM is not phosphorylated but associates with ACT, a member of the LIM-only class of proteins that has intrinsic transcriptional activity. Thus, in some circumstance, CREM can bypass the classical requirement for phosphorylation and association with CBP.
De Cesare
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Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS-INSERM, Université Louis Pasteur, Illkirch, Strasbourg, France.
Fimia
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GM
Sassone-Corsi
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D000818:Animals; D051786:Cyclic AMP Response Element Modulator; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D012097:Repressor Proteins; D015398:Signal Transduction; D013091:Spermatogenesis / Q000235:genetics*; D013094:Spermatozoa / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D051786:Cyclic AMP Response Element Modulator