The p38/MAPK pathway regulates microtubule polymerization through phosphorylation of MAP4 and Op18 in hypoxic cells

Cell Mol Life Sci. 2010 Jan;67(2):321-33. doi: 10.1007/s00018-009-0187-z. Epub 2009 Nov 14.

Abstract

In both cardiomyocytes and HeLa cells, hypoxia (1% O(2)) quickly leads to microtubule disruption, but little is known about how microtubule dynamics change during the early stages of hypoxia. We demonstrate that microtubule associated protein 4 (MAP4) phosphorylation increases while oncoprotein 18/stathmin (Op18) phosphorylation decreases after hypoxia, but their protein levels do not change. p38/MAPK activity increases quickly after hypoxia concomitant with MAP4 phosphorylation, and the activated p38/MAPK signaling leads to MAP4 phosphorylation and to Op18 dephosphorylation, both of which induce microtubule disruption. We confirmed the interaction between phospho-p38 and MAP4 using immunoprecipitation and found that SB203580, a p38/MAPK inhibitor, increases and MKK6(Glu) overexpression decreases hypoxic cell viability. Our results demonstrate that hypoxia induces microtubule depolymerization and decreased cell viability via the activation of the p38/MAPK signaling pathway and changes the phosphorylation levels of its downstream effectors, MAP4 and Op18.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaerobiosis
  • Animals
  • Cell Hypoxia
  • Cell Survival
  • HeLa Cells
  • Humans
  • Hypoxia / metabolism*
  • Microtubule-Associated Proteins / metabolism*
  • Microtubules / enzymology
  • Microtubules / metabolism*
  • Myocytes, Cardiac / metabolism*
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Stathmin / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Microtubule-Associated Proteins
  • Stathmin
  • p38 Mitogen-Activated Protein Kinases