title: Tethering function of the caspase cleavage fragment of Golgi protein p115 promotes apoptosis via a p53-dependent pathway.
abstract: The Golgi apparatus undergoes extensive fragmentation during apoptosis due in part to caspase-mediated cleavage of its structural proteins. Significantly, the Golgi-vesicle-tethering protein p115 is cleaved at Asp(757) early during apoptosis and the nuclear translocation of its 205 amino acid C-terminal fragment (CTF) precedes observable Golgi fragmentation. Nuclear localization of the p115 CTF induces apoptosis. The regulation of CTF nuclear translocation and the mechanism of its apoptotic activity however, remain unknown. Here, we demonstrate that nuclear translocation of the CTF is regulated by SUMOylation. CTF-induced apoptosis is transcription dependent and mediated by the tumor suppressor, p53. Expression of the CTF led to the phosphorylation and stabilization of p53 and results in the expression of PUMA, a pro-apoptotic target of p53. CTF-induced stabilization of p53 is sensitive to the MEK/ERK inhibitor U0126. Co-immunoprecipitation studies indicate that the p115 CTF can bind to both p53 and ERK1. The CTF is also able to form dimers and its dimerization is dependent on residues 859-884, previously determined to be required for apoptosis. Indeed, CTF expression promotes p53-ERK interaction, which is diminished upon deletion of residues 859-884. Together, our results indicate a conserved tethering function of the Golgi protein p115 CTF which promotes p53-ERK interaction for the amplification of the apoptotic signal.
authors.affiliation: From the Departments of Developmental and Molecular Biology and. Electronic address: pohchoo.how@med.einstein.yu.edu.
authors.forename: Poh Choo
authors.initials: PC
authors.lastname: How
authors.affiliation: From the Departments of Developmental and Molecular Biology and; Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Dennis
authors.initials: D
authors.lastname: Shields
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism*; D000077614:Golgi Matrix Proteins; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding; D055550:Protein Stability; D058207:Sumoylation / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000077614:Golgi Matrix Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D033921:Vesicular Transport Proteins; C091580:vesicular transport factor p115; D020169:Caspases