Linking Microtubule Dynamics to HIF-1α

Science's STKE  04 Mar 2003:
Vol. 2003, Issue 172, pp. tw91-TW91
DOI: 10.1126/stke.2003.172.tw91

Cells call upon the transcription factor nuclear factor kappa B (NF-κB) to alter gene expression in response to stressful conditions. Although cytoskeletal reorganization is a normal and dynamic process, disruption of microtubules correlates with increased NF-κB activity as well. Jung et al. report that this correlation can be further linked to increased expression of the transcription factor hypoxia-inducible factor-1 alpha (HIF-1α). HIF-1α activity is regulated by the ubiquitin-proteasome pathway. Hypoxic conditions prevent its destruction, allowing HIF-1α to enter the nucleus and activate genes that promote cell survival. When a variety of mammalian cells were treated with microtubule-depolymerizing agents (MDAs), NF-κB activity and HIF-1α protein expression increased. Inhibition of NF-κB with drugs or by expression of a repressor protein blocked this effect, and other transcription factors did not mediate the effect of MDAs on HIF-1α. A cell line that is resistant to the disrupting effect of MDAs displayed normal NF-κB activity but was unable to raise HIF-1α expression in response to MDA treatment. Transcription inhibitors also blocked the effect of MDAs on HIF-1α expression, indicating that this nonhypoxic signaling pathway between microtubules and the gene targets of HIF-1α is distinct from the hypoxia-induced pathway that regulates HIF-1α stability, and could participate in cytoskeletal remodeling during normal and tumorigenic processes.

Y.-J. Junh, J.S. Isaacs, S. Lee, J. Trepel, L. Neckers, Microtubule disruption utilizes an NFκB-dependent pathway to stabilize HIF-1α protein. J. Biol. Chem. 278, 7445-7452 (2003). [Abstract] [Full Text]