The Semenza lab studies molecular mechanisms underlying angiogenesis and vascular remodeling in ischemic cardiovascular disease. A major aspect of this process is the production of multiple angiogenic cytokines and growth factors in response to hypoxia/ischemia, which is mediated by the transcription factor HIF-1 (hypoxia-inducible factor 1). HIF-1 mediates vascular and progenitor cell responses to angiogenic signals, but these processes are impaired by aging and diabetes. The team currently is studying the use of gene and stem cell therapy in mouse models of critical limb ischemia and cutaneous burn wounds.
HIF-1 plays important roles in critical aspects of cancer biology, including tumor angiogenesis, regulation of glucose and energy metabolism, invasion, and metastasis. The team is taking several approaches to inhibit HIF-1 activity, including RNA interference, dominant negative constructs, and small molecule inhibitors. A major focus of their current cancer research is using animal, cell-based, molecular, and biophysical approaches to investigate the role of HIF-1 in vascular and lymphatic metastasis of human breast cancer.
HIF-1 also is required for ischemic preconditioning, short episodes of ischemia and reperfusion that protect the heart against a subsequent prolonged ischemic insult. The team currently is exploring the cellular and molecular mechanisms underlying ischemic preconditioning using mice in which HIF-1 activity has been knocked out in specific cell types within the heart.
The team now is using mass spectroscopy techniques to identify proteins that interact with the HIF-1 subunit. By employing this taking proteomics-based approach, they have identified novel regulators of HIF-1 transcriptional activity as well as direct regulation of the DNA replication machinery by HIF-1.
- Luo W, Lin B, Wang Y, Zhong J, O'Meally R, Cole RN, Pandey A, Levchenko A, Semenza GL. PHD3-mediated prolyl hydroxylation of non-muscle actin impairs polymerization and cell motility. Mol Biol Cell. 2014 Jul 30. pii: mbc.E14-02-0775. [Epub ahead of print] PMID: 25079693
- Hubbi ME, Gilkes DM, Hu H, Kshitiz, Ahmed I, Semenza GL. Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression. Proc Natl Acad Sci U S A. 2014 Jul 28. pii: 201412840. [Epub ahead of print] PMID: 25071185
- Takano N, Sarfraz Y, Gilkes DM, Chaturvedi P, Xiang L, Suematsu M, Zagzag D, Semenza GL. Decreased Expression of Cystathionine β-Synthase Promotes Glioma Tumorigenesis. Mol Cancer Res. 2014 Jul 3. pii: molcanres.0184.2014. [Epub ahead of print] PMID: 24994751
- Peng YJ, Yuan G, Khan S, Nanduri J, Makarenko VV, Reddy VD, Vasavda C, Kumar GK, Semenza GL, Prabhakar NR. Regulation of hypoxia-inducible factor-α isoforms and redox state by carotid body neural activity in rats. J Physiol. 2014 Jun 27. [Epub ahead of print] PMID: 24973414
- Wang T, Gilkes DM, Takano N, Xiang L, Luo W, Bishop CJ, Chaturvedi P, Green JJ, Semenza GL. Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci U S A. 2014 Jun 17. pii: 201410041. [Epub ahead of print] PMID: 24938788