Adrenergic signals direct rhythmic expression of transcriptional represser CREM in the pineal gland

Abstract

Transcription factor CREM appears to play a key physiological and developmental role within the hypothalamic-pituitary-gonadal axis. This axis is modulated by the pineal hormone melatonin, whose production is in turn driven by the endogenous clock. There is striking circadian fluctuation of a novel CREM isoform, ICER, which is expressed at high levels during the night. ICER is generated from an alternative, intronic promoter and functions as a powerful repressor of cyclic AMP-induced transcription. Rhythmic adrenergic signals originated by the clock direct ICER expression by stimulation of the cAMP signal transduction pathway.

ICER-IIγ is a tumor suppressor that mediates the antiproliferative activity of cAMP

“…One such gene is the c-fos proto-oncogene. We have previously shown that ICER repressed the CRE in c-fos promoter Stehle et al, 1993). This datum suggested to us that ICER modulated c-fos gene expression in the AtT20 cell lines.…”

“…Conversely, c-fos mRNA was super-induced in cells over-expressing the antisense ICER-IIg cDNA. Previous data (Stehle et al, 1993) strongly suggest that this inhibition is achieved by direct binding of ICERIIg to the CRE in the c-fos promoter. Moreover we have recently reported that the expression of cyclin A was also regulated by ICER-IIg (Lamas et al, 1997) and cAMP levels (Desdouets et al, 1995).…”

“…In the nucleus the cAMP pathway uses cAMP-responsive element binding proteins to mediate gene expression (reviewed by Habener, 1990;Vallejo, 1994;Molina, 1997). The CREM gene is of special interest since its expression is strongly induced by cAMP Stehle et al, 1993). The induced isoform, termed ICER is a powerful repressor of the cAMP-mediated gene expression.…”

The transcriptional repressor ICER and cAMP-induced programmed cell death

“…The kinetics of cAMP induction place ICER as a key player in the early cellular response to hormonal stimuli. It has been shown that ICER is predominantly expressed in neuroendocrine tissues Stehle et al, 1993;Monaco et al, 1995;Lalli and Sassone-Corsi, 1995).…”

“…By a process of extensive alternative splicing, the CREM gene generates a family of both activator and repressor isoforms (Delmas et al, 1992;Foulkes et al, 1991, 1992a,b, Laiode et al, 1993. Using an alternative intronic promoter the CREM gene also generates the powerful repressor, ICER Stehle et al, 1993). The ICER speci®c promoter (P2) contains tandemly repeated CRE-like elements and is rapidly and strongly induced upon activation of the cAMP pathway.…”