Hypoxic regulation of Id-1 and activation of the unfolded protein response are aberrant in neuroblastoma.
The Id proteins play an important role in proliferation, differentiation and tumorigenesis. Many tumors are hypoxic, but it is unknown if expression of Id proteins is regulated in hypoxic cells. Here we show that Id-1 is down-regulated in multiple primary, immortalized, and neoplastic hypoxic cell lines, and the transcriptional repressor ATF-3 is both necessary and sufficient for this hypoxia-induced repression of Id-1. Hypoxic up-regulation of ATF-3 is due in part to activation of the unfolded protein response, a cellular stress response. Remarkably, we observe that the unfolded protein response is de-regulated in all neuroblastoma cell lines tested. Indeed, in the absence of ATF-3 the hypoxia-induced transcription factor HIF-1 up-regulates Id-1 in hypoxic neuroblastoma cells. Hypoxic neuroblastoma cells diminish expression of some neuronal differentiation markers, and forced expression of ATF-3 in hypoxic neuroblastoma cells represses Id-1 and prevents the loss of these markers. The divergent regulation of Id proteins in distinct hypoxic cells may explain some of the varied effects hypoxia has on cellular differentiation and proliferation.
Nemetski
S Maureen
SM
Department of Medicine, Pharmacology and the New York University Cancer Institute, The New York University School of Medicine, New York City, New York 10016, USA.
Gardner
Lawrence B
LB
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D015536:Down-Regulation; D006801:Humans; D000860:Hypoxia; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009447:Neuroblastoma / Q000378:metabolism*; D011489:Protein Denaturation; D017510:Protein Folding; D014158:Transcription, Genetic; D015854:Up-Regulation
C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1