HIF-1 beta - activating gene transcription in response to hypoxia

Wed, 05/06/2015 - 14:43

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor consisting of alpha and beta subunits. The levels of functional HIF-1 in the cell depends on the level of oxygen allowing cells to respond to hypoxic conditions. HIF-1α is a ubiquitously expressed protein containing an oxygen-dependent degradation domain that under normal conditions regulates its constant degradation. HIF-1 beta, on the other hand, is a stable constitutively expressed protein that localizes to the nucleus. Upon stabilization of HIF-1α by low oxygen it translocates to the nucleus where it dimerizes with HIF-1 beta to form an active transcription factor. HIF-1 recognizes and binds to hypoxia response elements (HRE) in the promoters of target genes including those involved in angiogenesis and cell proliferation such as vascular endothelial growth factor (VEGF) and erythropoietin.

The Semenza group from Johns Hopkins examined the role of RhoA and Rho kinase 1, two regulators of cell motility, in breast cancer cells (1). Through ChIP assays with the HIF-1β antibody they demonstrated HIF-1 mediates transcriptional activation of cell motility genes in response to hypoxia. They also showed HIF-1, RhoA, and Rho kinase 1 levels correlate with metastatic status of tumors. In a study by Sena et al. hypoxia-induction of HIF-1 was shown to be dependent on the SWI/SNF chromatin remodeling complex (2). Using ChIP assays with the HIF-1β antibody the group demonstrated SWI/SNF complexes are recruited by HIF-1α/β to promote increased transcription of HIF-1α. While studying the differentiation of multipotential stromal cells the Sen group showed HIF-1 signaling enhances cell proliferation and growth factor secretion (3). By depleting HIF-1α/β and confirming knockdown with the HIF-1β antibody they were able to encourage osteogenic differentiation. While HIF-1 expression is thought to be constitutive, a study by Zhang et al. demonstrated HIF-1 mRNA levels can be regulated post-transcriptionally (4). Their study showed HIF-1α mRNA is stabilized by JNK signalling. They monitored changes in HIF-1α protein levels through western blotting and used the HIF-1 beta antibody as an internal loading control. Pawlus et al. from the University of Colorado examined the role of signal transducer and activator of transcription-3 (STAT3) on HIF-1 activation in the hypoxic tumor microenvironment (5). They monitored HIF-1 levels by western blotting using the HIF-1β antibody. STAT3 inhibitors blocked induction of HIF-1α while leaving HIF-1 beta unaffected. These experiments demonstrated the usefulness of STAT3 inhibitors by allowing the targeting both the HIF-1 and STAT3 pathways simultaneously.

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