• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

Deactylase inhibitors disrupt cellular complexes containing protein phosphatases and deacetylases.

Affinity isolation of protein serine/threonine phosphatases on the immobilized phosphatase inhibitor microcystin-LR identified histone deacetylase 1(HDAC1), HDAC6, and HDAC10 as novel components of cellular phosphatase complexes. Other HDACs, specifically HDAC2, -3, -4, and -5, were excluded from such complexes. In vitro biochemical studies showed that recombinant HDAC6, but not HDAC4, bound directly to the protein phosphatase (PP)1 catalytic subunit. No association was observed between HDAC6 and PP2A, another major protein phosphatase. PP1 binding was mapped to the second catalytic domain and adjacent C-terminal sequences in HDAC6, and treatment of cells with trichostatin A (TSA) disrupted endogenous HDAC6.PP1 complexes. Consistent with the inhibition of tubulin deactylase activity of HDAC6, TSA enhanced cellular tubulin acetylation, and acetylated tubulin was present in the PP1 complexes from TSA-treated cells. Trapoxin B, a weak HDAC6 inhibitor, and calyculin A, a cell-permeable phosphatase inhibitor, had no effect on the stability of the HDAC6.PP1 complexes or on tubulin acetylation. Mutations that inactivated HDAC6 prevented its incorporation into cellular PP1 complexes and suggested that when bound together both enzymes were active. Interestingly, TSA disrupted all the cellular HDAC.phosphatase complexes analyzed. This study provided new insight into the mechanism by which HDAC inhibitors elicited coordinate changes in cellular protein phosphorylation and acetylation and suggested that changes in these protein modifications at multiple subcellular sites may contribute to the known ability of HDAC inhibitors to suppress cell growth and transformation.

Pubmed ID: 14670976

Authors

  • Brush MH
  • Guardiola A
  • Connor JH
  • Yao TP
  • Shenolikar S

Journal

The Journal of biological chemistry

Publication Data

February 27, 2004

Associated Grants

  • Agency: NIDDK NIH HHS, Id: R01-DK52054

Mesh Terms

  • Acetylation
  • Animals
  • Binding Sites
  • Cell Line
  • Cells
  • Enzyme Inhibitors
  • Gene Expression
  • Histone Deacetylase 1
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases
  • Humans
  • Hydroxamic Acids
  • Mutagenesis, Site-Directed
  • Phosphoprotein Phosphatases
  • Phosphorylation
  • Rabbits
  • Transfection
  • Tubulin