The human SNF5/INI1 protein facilitates the function of the growth arrest and DNA damage-inducible protein (GADD34) and modulates GADD34-bound protein phosphatase-1 activity.
The growth arrest and DNA damage-inducible protein (GADD34) mediates growth arrest and apoptosis in response to DNA damage, negative growth signals, and protein malfolding. GADD34 binds to protein phosphatase-1 (PP1) and can attenuate translational elongation of key transcriptional factors through dephosphorylation of eukaryotic initiation factor-2alpha. We reported previously that the ... human trithorax leukemia fusion protein (HRX) can bind to GADD34 and abrogate GADD34-mediated apoptosis in response to UV irradiation. We found that hSNF5/INI1, a component of the hSWI/SNF chromatin remodeling complex, also binds to GADD34 and can coexist with GADD34 and HRX fusion proteins as a trimolecular complexes in vivo. In the present report, we demonstrate that hSNF5/INI1 binds to GADD34 in part through the PP1 docking site within a domain homologous to herpes simplex virus-1 ICP34.5. We found that hSNF5/INI1 can bind PP1 independently and weakly stimulate its phosphatase activity in solution and in complex with GADD34. hSNF5/INI1 and PP1 do not compete for binding to GADD34 but rather form a stable heterotrimeric complex with GADD34. We also show that Epstein-Barr nuclear protein 2, which binds hSNF5/INI1, can disrupt hSNF5/INI1 binding to GADD34 and partially reverse the GADD34-mediated growth suppression function in Ha-ras expressing HIH-3T3 (3T3-ras) cells. These results implicate hSNF5/INI1 in the function of GADD34 and suggest that hSNF5/INI1 may regulate PP1 activity in vivo.
Mesh Terms:
3T3 Cells, Amino Acid Sequence, Animals, Antigens, Differentiation, Binding Sites, Cell Cycle Proteins, Cell Division, Cell Line, Cell Survival, Chromosomal Proteins, Non-Histone, Cloning, Molecular, DNA Damage, DNA-Binding Proteins, Humans, Mice, Molecular Sequence Data, Peptide Fragments, Phosphoprotein Phosphatases, Protein Phosphatase 1, Proteins, Recombinant Fusion Proteins, Recombinant Proteins, Transcription Factors, Transfection
3T3 Cells, Amino Acid Sequence, Animals, Antigens, Differentiation, Binding Sites, Cell Cycle Proteins, Cell Division, Cell Line, Cell Survival, Chromosomal Proteins, Non-Histone, Cloning, Molecular, DNA Damage, DNA-Binding Proteins, Humans, Mice, Molecular Sequence Data, Peptide Fragments, Phosphoprotein Phosphatases, Protein Phosphatase 1, Proteins, Recombinant Fusion Proteins, Recombinant Proteins, Transcription Factors, Transfection
J. Biol. Chem.
Date: Aug. 02, 2002
PubMed ID: 12016208
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