ICER expression inhibits leukemia phenotype and controls tumor progression.
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 in the majority of childhood leukemias contributing to disease progression, whereas ICER, its endogenous repressor, was found to be downregulated. Our research focus has been the function of restored ICER expression. ICER exogenously expressed in cell 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 HL60 to preserve CREB overexpression, which disrupts normal myelopoiesis and promotes blast proliferation. These findings define the function of ICER as a tumor suppressor in leukemia. Unbalanced CREB/ICER expression needs to be considered a pathogenetic feature in leukemogenesis. The molecular characterization of this pathway could be useful for novel therapeutic strategies.
Pigazzi
M
M
Department of Pediatrics, Laboratory of Oncohematology, University of Padova, Padova, Italy. martina.pigazzi@unipd.it
Manara
E
E
Baron
E
E
Basso
G
G
D000818:Animals; D001752:Blast Crisis / Q000235:genetics; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics* / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
C115163:CREB1 protein, human; C497410:CREM protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D051786:Cyclic AMP Response Element Modulator; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex