title: Chromatin modifying protein 1A (Chmp1A) of the endosomal sorting complex required for transport (ESCRT)-III family activates ataxia telangiectasia mutated (ATM) for PanC-1 cell growth inhibition.
abstract: Chromatin modifying protein 1A (Chmp1A) is a member of the Endosormal sorting complex required for transport (ESCRT)-III family whose over-expression induces growth inhibition, chromatin condensation, and p53 phosphorylation. p53 is a substrate for Ataxia telangiectasia mutated (ATM), which can be activated upon chromatin condensation. Thus, we propose that Chmp1A regulates ATM, and the nuclear localization signal (NLS) is required for ATM activation. Our data demonstrated that over-expression of full-length Chmp1A induced an increase in active, phosphorylated ATM in the nucleus, where they co-localized. It also induced an increase in phospho-p53 in the nucleus, and in vitro ATM kinase and p53 reporter activities. The intensity of phospho-p53 closely followed that of ectopically induced full-length Chmp1A, suggesting a tight correlation between Chmp1A over-expression and p53 phosphorylation. On the other hand, Chmp1A depletion (reported to promote cell growth) had minor effects on phospho-ATM and p53 expression compared to control, which had very little expression of these proteins. NLS-deleted cells showed uniform cytoplasmic-Chmp1A expression and acted like shRNA-expressing cells (cell growth promotion and minimal effect on ATM), demonstrating the significance of NLS on ATM activation and growth inhibition. C-deleted Chmp1A, detected in the cytoplasm at the enlarged vesicles, increased phospho-ATM and p53, and inhibited growth; yet it had no effect on in vitro ATM kinase or p53 reporter activities, suggesting that the C-domain is not required for ATM activation. Finally, ATM inactivation considerably reduced Chmp1A mediated growth inhibition and phosphorylation of p53, showing that Chmp1A regulates tumor growth partly through ATM signaling.
authors.affiliation: Department of Biology, West Virginia State University, Institute, WV, USA.
authors.forename: Sumanth
authors.initials: S
authors.lastname: Manohar
authors.forename: Matthew
authors.initials: M
authors.lastname: Harlow
authors.forename: Hahn
authors.initials: H
authors.lastname: Nguyen
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Hankins
authors.forename: Maiyon
authors.initials: M
authors.lastname: Park
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D033921:Vesicular Transport Proteins
chemical_list: C443709:CHMP1A protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D033921:Vesicular Transport Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases