Microtubule disruption targets HIF-1α mRNA to cytoplasmic P-bodies for translational repression Academic Article uri icon

Overview

MeSH Major

  • Cytoplasmic Structures
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Microtubules
  • Protein Biosynthesis
  • RNA Transport

abstract

  • The hypoxia inducible factor 1α (HIF-1α) is overexpressed in solid tumors, driving tumor angiogenesis and survival. However, the mechanisms regulating HIF-1α expression in solid tumors are not fully understood. In this study, we find that microtubule integrity and dynamics are intricately involved in orchestrating HIF-1α translation. HIF-1α messenger RNA (mRNA) traffics on dynamic microtubules when it is actively translated. Microtubule perturbation by taxol (TX) and other microtubule-targeting drugs stalls HIF-1α mRNA transport and releases it from polysomes, suppressing its translation. Immunoprecipitation of the P-body component Argonaute 2 (Ago2) after microtubule disruption shows significant enrichment of HIF-1α mRNAs and HIF-targeting microRNAs (miRNAs). Inhibition of HIF-repressing miRNAs or Ago2 knockdown abrogates TX's ability to suppress HIF-1α translation. Interestingly, microtubule repolymerization after nocodazole washout allows HIF-1α mRNA to reenter active translation, suggesting that microtubule dynamics exert tight yet reversible control over HIF-1α translation. Collectively, we provide evidence for a new mechanism of microtubule-dependent HIF-1α translation with important implications for cell biology.

publication date

  • January 10, 2011

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3019555

Digital Object Identifier (DOI)

  • 10.1083/jcb.201004145

PubMed ID

  • 21220510

Additional Document Info

start page

  • 83

end page

  • 99

volume

  • 192

number

  • 1