ATM is the primary kinase responsible for phosphorylation of Hsp90α after ionizing radiation
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Ameer L. Elaimy1, Aarif Ahsan1, Katherine Marsh1, William B. Pratt2, Dipankar Ray1, Theodore S. Lawrence1, Mukesh K. Nyati1
1Department of Radiation Oncology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
2Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
Mukesh K. Nyati, email: [email protected]
Keywords: Hsp90α, ionizing radiation, γH2AX, ATM, radiosensitization
Received: August 26, 2016 Accepted: October 05, 2016 Published: October 11, 2016
Heat shock protein 90 is a chaperone that plays an essential role in the stabilization of a large number of signal transduction molecules, many of which are associated with oncogenesis. An Hsp90 isoform (Hsp90α) has been shown to be selectively phosphorylated on two N-terminal threonine residues (threonine 5 and 7) and is involved in the DNA damage response and apoptosis. However, the kinase that phosphorylates Hsp90α after ionizing radiation (IR) and its role in post-radiation DNA repair remains unclear. Inasmuch as several proteins of the DNA damage response machinery are Hsp90 clients, the functional consequences of Hsp90α phosphorylation following IR have implications for the design of novel radiosensitizing agents that specifically target the Hsp90α isoform. Here we show that ATM phosphorylates Hsp90α at the T5/7 residues immediately after IR. The kinetics of Hsp90α T5/7 phosphorylation correlate with the kinetics of H2AX S139 phosphorylation (γH2AX). Although Hsp90α is located in both the cytoplasm and nucleus, only nuclear Hsp90α is phosphorylated by ATM after IR. The siRNA mediated knockdown of Hsp90α sensitizes head and neck squamous cell carcinoma cells, lung cancer cells and lung fibroblasts to IR. Furthermore, MEF cells that are Hsp90α null have reduced levels of γH2AX indicating that Hsp90α is important for the formation of γH2AX. Thus, this study provides evidence that Hsp90α is a component of the signal transduction events mediated by ATM following IR, and that Hsp90α loss decreases γH2AX levels. This work supports additional investigation into Hsp90α T5/7 phosphorylation with the goal of developing targeted radiosensitizing therapies.
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