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

• Published in: The Journal of biological chemistry Vol. 277; no. 31; pp. 27706 - 27715
• Main Authors: Wu, Daniel Y., Tkachuck, Douglas C., Roberson, Rachel S., Schubach, William H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.08.2002; American Society for Biochemistry and Molecular Biology
• Subjects: 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 - metabolism; Humans; Mice; Molecular Sequence Data; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Phosphoprotein Phosphatases - antagonists & inhibitors; Protein Phosphatase 1; Proteins - metabolism; Recombinant Fusion Proteins - metabolism; Recombinant Proteins - metabolism; SMARCB1 Protein; Transcription Factors; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M200955200

The growth arrest andDNA 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-2α. 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 complexesin 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.