Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis.
HIF-1, a hypoxia inducible transcription factor, plays a pivotal role in the cellular response to hypoxia by activating genes involved in glucose metabolism, vascular remodeling, and erythropoiesis. We identified Mxi1, a c-Myc antagonist, as a novel target gene induced in hypoxia. Mxi1 was not induced in cells deficient in ARNT (HIF-1beta), suggesting that Mxi1 is a transcriptional target of the HIF-1 complex. Notably, c-Myc protein levels decreased during hypoxia but were stabilized by a proteasome inhibitor. Analysis of downstream transcriptional targets of c-Myc during hypoxia revealed that genes regulated by c-Myc, such as ornithine decarboxylase (ODC), were downregulated during hypoxia. In contrast, genes that are regulated by c-Myc and HIF-1, such as LDH-A, were upregulated. Mxi1 protects against c-Myc-dependent sensitization to hypoxia-induced apoptosis. The results suggest a coordinated mechanism for opposing c-Myc signaling during hypoxia that is mediated by a reduction in c-Myc levels, the induction of Mxi1, and a dominant effect of HIF-1 transcriptional activity.
Corn
Paul G
PG
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Ricci
M Stacey
MS
Scata
Kimberly A
KA
Arsham
Andrew M
AM
Simon
M Celeste
MC
Dicker
David T
DT
El-Deiry
Wafik S
WS
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; C079440:MXI1 protein, human; C512788:Mxi1 protein, mouse