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Nuclear‐mediated function of Chmp1A in the regulation of ATM signaling activity for the control of human pancreatic tumor cell growth
Author(s) -
Manohar Sumanth,
Harlow Matthew,
Mackie Christopher Ryan,
Li Jing,
Park Maiyon
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.515.5
Subject(s) - chromatin , nuclear localization sequence , cell growth , kinase , microbiology and biotechnology , signal transduction , nls , cell cycle , chemistry , biology , cancer research , cell , biochemistry , nucleus , gene
Chmp1A is a member of the ESCRT‐III family that functions in the sorting of membrane proteins. Chmp1A was shown to regulate cell cycle progression and chromatin condensation. We recently reported that Chmp1A functions as a tumor suppressor by regulating P53 in pancreatic tumor cells. P53 is a substrate of ataxia‐telangiectasia mutated (ATM) kinase and the dynamics of ATM activation is closely related to chromatin modification. Thus, we hypothesize that Chmp1A, through its nuclear localization, regulates ATM signaling activity and subsequently pancreatic tumor growth. Our preliminary data indicates that Chmp1A overexpression led to an increase in phospho‐ATM. Immuno‐staining identified the co‐localization of ectopically induced Chmp1A with phospho‐ATM and P53 whose intensity closely reflected that of Chmp1A expression. ATM kinase assay indicates that Chmp1A overexpression increased ATM kinase activity as shown by an increase in the level of phospho‐P53 compared to control. In addition, ATM inhibitor‐treatment partly abolished Chmp1A mediated‐growth inhibition and P53 stabilization. We are testing the significance of nuclear localization signal (NLS) of Chmp1A by using various deletion constructs. We will discuss the significance of the NLS domain of Chmp1A on signaling activity of ATM and P53, and tumor cell growth. This research is supported by NIH 5P20RR016477, WV‐INBRE and RR020180‐02, COBRE.