Dynamic balancing of the dual nature of HIF-1alpha for cell survival.
In hypoxic cells, HIF-1alpha escapes from oxygen-dependent proteolysis and binds to the hypoxia-responsive element (HRE) for transcriptional activation of target genes involved in angiogenesis and glycolysis. We recently demonstrated that the G(1) checkpoint gene p21(cip1)is activated by HIF-1alpha with a novel mechanism that involves the HIF-1alpha PAS domains to displace Myc binding from p21(cip1) promoter. This HIF-1alpha-Myc pathway may account for up- and down-regulation of other hypoxia-responsive genes that lack the HRE. Moreover, the role of HIF-1alpha in cell cycle control indicates a dual, yet seemingly conflicting, nature of HIF-1alpha: promoting cell growth and arrest in concomitance. We speculate that a dynamic balance between the two processes is achieved by a "stop-and-go" strategy to maintain cell growth and survival. Tumor cells may adopt such scheme to evade the killing by chemotherapeutic agents.
Koshiji
Minori
M
Laboratory of Human Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Huang
L Eric
LE
D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D049108:Cell Enlargement / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism
D018797:Cell Cycle Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc