Cell Cycle Regulation of Cyclin A Gene Expression by the Cyclic AMP-Responsive Transcription Factors CREB and CREM

Abstract

Cyclin A is a pivotal regulatory protein which, in mammalian cells, is involved in the S phase of the cell cycle. Transcription of the human cyclin A gene is cell cycle regulated. We have investigated the role of the cyclic AMP (cAMP)-dependent signalling pathway in this cell cycle-dependent control. In human diploid fibroblasts (Hs 27), induction of cyclin A gene expression at G 1 /S is stimulated by 8-bromo-cAMP and suppressed by the protein kinase A inhibitor H89, which was found to delay S phase entry. Transfection experiments showed that the cyclin A promoter is inducible by activation of the adenylyl cyclase signalling pathway. Stimulation is mediated predominantly via a cAMP response element (CRE) located at positions ؊80 to ؊73 with respect to the transcription initiation site and is able to bind CRE-binding proteins and CRE modulators. Moreover, activation by phosphorylation of the activators CRE-binding proteins and CRE modulator and levels of the inducible cAMP early repressor are cell cycle regulated, which is consistent with the pattern of cyclin A inducibility by cAMP during the cell cycle. These results suggest that the CRE is, at least partly, implicated in stimulation of cyclin A transcription at G 1 /S.Cyclins are a group of proteins which are periodically synthesized and degraded during the cell cycle. This enables them to activate at appropriate times the cyclin-dependent kinases (cdks), whose activity is needed to drive the cells through the cell cycle (for recent reviews, see references 5, 37, and 41).In higher eukaryotes, cyclin proteins have been classified as A-, B-, C-, D-, E-, or G-type according to sequence comparison. A-and B-type cyclins associate with cdc2 (cdk1), whose activity is required for entry into mitosis (47). Additional cyclins, which function earlier in the cell cycle, have been identified more recently. D-type cyclins are involved in G 1 progression (33) in association with cdk4 and cdk6. Cyclin E has been implicated in the initiation of DNA replication and is associated with cdk2 at the G 1 /S transition (12, 28).

Cyclic AMP signalling pathway and cellular proliferation: induction of CREM during liver regeneration

“…The markedly transient induction of ICER protein following PH, which di ers from that observed in other systems (Lalli and Sassone-Corsi, 1995;Monaco et al, 1995), may suggest a distinct function. We have recently described the involvement of CREM gene products in the regulation of cyclin A gene and possibly cell cycle (Desdouets et al, 1995). In addition, ablation of the CREM gene in the mouse germline by homologous recombination results in an arrest of postmeiotic male germ cell di erentiation and an increase in apoptosis (Nantel et al, 1996).…”

“…The use of an alternative promoter (P2) lying near the 3' end of the gene, generates the cAMP-inducible repressor isoform ICER (Inducible cAMP Early Repressor) . Elevated ICER expression is characteristic of neuroendocrine tissues (SassoneCorsi, 1995).…”

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

“…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). ICER-IIg down-regulated cyclin A RNA expression by binding to the CRE in cyclin A promoter.…”

Gdnf signaling pathways within the mammalian spermatogonial stem cell niche

“…Cyclin A1 is highly expressed in pachytene spermatocytes and required for meiosis, and Cyclin A2 is mostly present in type A spermatogonia, including the SSCs Ravnik and Wolgemuth, 1999). Therefore, like in other cell types, Creb and c-Fos enhance the expression of cyclin A and favors the G1/S cell cycle transition in Gfrα-1 positive spermatogonia (Desdouets et al, 1995;Sunters et al, 2004). Taken together, our studies of the effects of Gdnf on SSCs indicate that multiple signaling pathways are responsible for their self-renewal and maintenance.…”