The expanding family of CREB/CREM transcription factors that are involved with spermatogenesis

Jeremy Don, Gil Stelzer

Research output: Contribution to journalArticlepeer-review

162 Scopus citations

Abstract

One of the molecular mechanisms shown to have played a major role in orchestrating the expression of the many genes with unique cellular and temporal specificity in spermatogenesis, is the cAMP-dependent signaling pathway. In this pathway, gene expression is mediated primarily by two members of the bZIP transcription factors-cAMP-response element binding protein (CREB) and cAMP-responsive element modulator (CREM). Both bind a specific cis element, cAMP-response element (CRE), in the promoter of target genes, both are activated by protein kinase A (PKA) phosphorylation that enables binding of CREB binding protein (CBP) and recruitment of the basal transcription machinery, and both are characterized by multiple alternatively spliced forms. Some of these alternatively spliced forms lack the transactivation domains and hence function as transcription suppressors. In Sertoli cells, CREB levels fluctuate in a cyclical manner that depends on the specific cell associations along the spermatogenic wave. Follicle stimulating hormone (FSH) activates the cAMP signaling pathway and consequently, CREB positively auto-regulates its own expression (by binding to a CRE like element in its promoter). Subsequently, activated CREB activates transcription of genes essential for proper germ cell differentiation. In addition, TNFα secreted by round spermatids, activates NF-κB dependent CREB expression in Sertoli cells and thus, contributes to the elevated CREB levels as long as these cells are intimately associated. Inducible cAMP early repressor (ICER), a suppressor isoform of CREM, also activated by CREB, down regulates CREB expression together with its own expression, resetting CREB to basal level that enables a new spermatogenic wave. In germ cells, antagonist forms of CREM (α, β and γ) are present in premeiotic cells and early prophase spermatocytes. A prominent switch to the CREMτ and CREMθ activating forms starts in pachytene spermatocytes leading to the activation of haploid genes important for spermiogenesis in round spermatids. Interestingly, in germ cells, CREM exerts activation of haploid genes independent of its phosphorylation state. It associates with activator of CREM in testis (ACT), that has an intrinsic transcriptional activity, rather than with CBP. These and other findings suggest that the expanding CREB/CREM proteins and potentially other members of the CREB family are key molecular regulators at all stages of spermatogenesis.

Original languageEnglish
Pages (from-to)115-124
Number of pages10
JournalMolecular and Cellular Endocrinology
Volume187
Issue number1-2
DOIs
StatePublished - 22 Feb 2002

Bibliographical note

Funding Information:
This work was supported by grant number 97-00318 from the United States-Israel Binational Science Foundation (BSF), Jerusalem, Israel. The authors are grateful to Avie Goldraich and Sharon Victor for reviewing the manuscript.

Funding

This work was supported by grant number 97-00318 from the United States-Israel Binational Science Foundation (BSF), Jerusalem, Israel. The authors are grateful to Avie Goldraich and Sharon Victor for reviewing the manuscript.

FundersFunder number
United States-Israel Binational Science Foundation

    Keywords

    • CREB
    • CREM
    • FSH
    • Germ cells
    • Sertoli cells
    • Spermatogenesis
    • Transcription factors
    • cAMP

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