Posttranslational nitrotyrosination of α-tubulin induces cell cycle arrest and inhibits proliferation of vascular smooth muscle cells

Anh D. Phung, Karel Soucek, Lukás Kubala, Richart W Harper, J. Chloë Bulinski, Jason P. Eiserich

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Hyperproliferation of vascular smooth muscle cells is a hallmark of atherosclerosis and related vascular complications. Microtubules are important for many aspects of mammalian cell responses including growth, migration and signaling. α-Tubulin, a component of the microtubule cytoskeleton, is unique amongst cellular proteins in that it undergoes a reversible posttranslational modification whereby the C-terminal tyrosine residue is removed (Glu-tubulin) and re-added (Tyr-tubulin). Whereas the reversible detyrosination/tyrosination cycle of α-tubulin has been implicated in regulating various aspects of cell biology, the precise function of this posttranslational modification has remained poorly characterized. Herein, we provide evidence suggesting that α-tubulin detyrosination is a required event in the proliferation of vascular smooth muscle cells. Proliferation of rat aortic smooth muscle cells in response to serum was temporally associated with the detyrosination of α-tubulin, but not acetylation of α-tubulin; Glu-tubulin reached maximal levels between 12 and 18 h following cell cycle initiation. Inclusion of 3-nitro-l-tyrosine (NO2Tyr) in the culture medium resulted in the selective nitrotyrosination of α-tubulin, that was paralleled by decreased elaboration of Glu-tubulin, decreased expression of cyclins A and E, decreased association of the microtubule plus-end binding protein EB1, and inhibited cell proliferation. Nitrotyrosination of α-tubulin did not induce necrotic or apoptotic death of rat aortic smooth muscle cells, but instead led to cell cycle arrest at the G1/S boundary coincident with decreased DNA synthesis. Collectively, these results suggest that the C-terminus of α-tubulin and its detyrosination are functionally important as a molecular switch that regulates cell cycle progression in vascular smooth muscle cells.

Original languageEnglish (US)
Pages (from-to)1241-1252
Number of pages12
JournalEuropean Journal of Cell Biology
Volume85
Issue number12
DOIs
StatePublished - Dec 7 2006

Keywords

  • Atherosclerosis
  • Cell cycle
  • Cytoskeleton
  • Detyrosination
  • Microtubules
  • Nitrotyrosination
  • Proliferation
  • Tubulin tyrosine ligase
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Anatomy
  • Cell Biology

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