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Functional Analysis of the Mouse ICER (Inducible cAMP Early Repressor) Promoter: Evidence for a Protein That Blocks Calcium Responsiveness of the CAREs (cAMP Autoregulatory Elements)

E. A. Doisy Department of Biochemistry and Molecular Biology Saint Louis University Health Sciences Center St. Louis, Missouri 63104

Although Ca²⁺ and cAMP mediate their effects through distinct pathways, both signals converge upon the phosphorylation of the cAMP response element (CRE) binding protein, CREB, thereby activating transcription of CRE-regulated genes. In WEHI7.2 thymocytes, cAMP increases the expression of the inducible cAMP early repressor (ICER) gene through CRE-like elements, known as cAMP autoregulatory elements (CAREs). Because Ca²⁺- and cAMP-mediated transcription converge in WEHI7.2 thymocytes, we examined the effect of Ca²⁺ fluxes on the expression of the ICER gene in these cells. Despite the presence of multiple CAREs within its promoter, ICER gene transcription was not activated by Ca²⁺. Moreover, Ca²⁺ attenuated the stimulatory effect of cAMP on ICER expression. Transient expression of reporter constructs demonstrated that when these CAREs were placed in a different DNA promoter context, the elements became responsive to Ca²⁺. Detailed studies using chimeric promoter constructs to map the region responsible for blocking the transcriptional response to Ca²⁺ indicated that a small portion of the ICER promoter was necessary for the effect. Southwestern blot analysis identified a 83-kDa nuclear protein that bound specifically to that region. The relative binding activity of the factor to the ICER promoter and mutant promoter sequences correlated with an inhibition of Ca²⁺-activated gene expression in WEHI7.2 cells. These data suggest that the factor functions as a putative Ca²⁺-activated repressor of CREB/CRE-mediated transcription. Thus, depending on the surrounding context in which the CRE is located, CREs of individual genes can be regulated separately by Ca²⁺ and cAMP despite the convergence of these two signaling pathways.

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