Alternative exon splicing controls a translational switch from activator to repressor isoforms of transcription factor CREB during spermatogenesis.
The cAMP/protein kinase A signaling pathway activates the cAMP-responsive transcription factor CREB. Here we describe a unique alternative RNA splicing event that occurs during the development of germ cells in the testis, resulting in a translational switch from an mRNA encoding activator CREB to an mRNA encoding novel inhibitor CREB isoforms (I-CREBs). Alternative splicing of an additional exon into the CREB mRNA in mid to late pachytene spermatocytes results in the premature termination of translation and consequent downstream reinitiation of translation producing I-CREBs. The I-CREBs down-regulate cAMP-activated gene expression by inhibiting activator CREB from binding to cAMP response elements. Further, the developmental stage-specific expression of I-CREBs in germ cells of the seminiferous tubules correlates with the cyclical down-regulation of activator CREB, suggesting that I-CREBs repress expression of the cAMP-inducible CREB gene as well as other genes transiently induced by cAMP during the 12-day cycle of spermatogenesis.
Walker
W H
WH
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02114, USA.
Girardet
C
C
Habener
J F
JF
D017398:Alternative Splicing; D001483:Base Sequence; D000242:Cyclic AMP / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D005091:Exons; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D012097:Repressor Proteins / Q000235:genetics*; D013091:Spermatogenesis; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D017362:Cyclic AMP Response Element-Binding Protein; D017931:DNA Primers; D012097:Repressor Proteins; D015534:Trans-Activators; D000242:Cyclic AMP