TRANSCRIPTION Linking Microtubule Dynamics to HIF-1

Cells call upon the transcription factor nuclear factor kappa B (NF-B) 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-B 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-1). HIF-1 activity is regulated by the ubiquitin-proteasome pathway. Hypoxic conditions prevent its destruction, allowing HIF-1 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-B activity and HIF-1 protein expression increased. Inhibition of NF-B 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-1. A cell line that is resistant to the disrupting effect of MDAs displayed normal NF-B activity but was unable to raise HIF-1 expression in response to MDA treatment. Transcription inhibitors also blocked the effect of MDAs on HIF-1 expression, indicating that this nonhypoxic signaling pathway between microtubules and the gene targets of HIF-1 is distinct from the hypoxia-induced pathway that regulates HIF-1 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 NFB-dependent pathway to stabilize HIF-1 protein. J. Biol. Chem. 278, 7445-7452 (2003). [Abstract] [Full Text]