PHOSPHORYLATION AND NEGATIVE REGULATION OF THE TRANSCRIPTIONAL ACTIVATOR CREM BY P34CDC2

Transcription factors that bind to cAMP-responsive elements (CREs) reg ulate the expression of target genes in response to activation of the adenylyl cyclase pathway. It is generally thought that activation is o btained through direct phosphorylation by the cAMP-dependent protein k inase-A. We have isolated the gene CRE modulator (CREM), which encodes multiple members of the CRE-binding protein family, by cell-specific alternative splicing. Various isoforms have been characterized, encodi ng both repressors (CREM alpha, -beta, and -gamma) as well as activato rs (CREM tau). Here we show that the function of the activator CREM ta u is regulated by the p34(cdc2) kinase. Multiple serine and threonine residues are phosphorylated in vivo as well as in vitro by p34(cdc2). Although there is no effect of p34(cdc2)-mediated phosphorylation on C REM tau DNA binding, we observed a dramatic effect on the trans-regula tory function. Coexpression of a constitutively active p34(cdc2) mutan t shows that the trans-activation potential of CREM tau is strongly re duced by p34(cdc2). This represents the first example of negative regu lation of a transcription factor of this class by p34(cdc2).