1390

CREM

CREM-2|ICER|hCREM-2;cAMP responsive element modulator;CREM;cAMP responsive element modulator

CREM 2alpha-b protein|CREM 2beta-a protein|cAMP response element modulator|cAMP-responsive element modulator|inducible cAMP early repressor ICER

10p11.21

protein-coding

The inducible cyclic AMP (cAMP) early repressor (ICER) and cAMP response element-binding protein (CREB) are transcriptional regulators of the cAMP-mediated signaling pathway. CREB has been demonstrated to be upregulated inthe majority of childhood leukemias contributing to disease progression, whereasICER, its endogenous repressor, was found to be downregulated. Our research focus has been the function of restored ICER expression. ICER exogenously expressed incell lines decreases CREB protein level and induces a lowered clonogenic potential in vitro. It decreases the ability of HL60 to invade the extramedullary sites and to promote bone marrow angiogenesis in nonobese diabetic-severe combined immunodeficient mice, demonstrating its potential effects on tumor progression. ICER represses the majority of 96 target genes upregulated by CREB.It binds CRE promoters and controls gene expression restoring the normal regulation of major cellular pathways. ICER is subjected to degradation through a constitutively active form of the extracellular signal-regulated protein kinase,which drives it to the proteasome. We propose that ICER is downregulated in HL60to preserve CREB overexpression, which disrupts normal myelopoiesis and promotesblast proliferation. These findings define the function of ICER as a tumor suppressor in leukemia. Unbalanced CREB/ICER expression needs to be considered apathogenetic feature in leukemogenesis. The molecular characterization of this pathway could be useful for novel therapeutic strategies.