Pharmacological inhibition of ATM by KU55933 stimulates ATM transcription

Hilal S. Khalil, Hemanth Tummala, Ted R. Hupp, Nikolai Zhelev

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Ataxia-telangiectasia mutated (ATM) kinase is a component of a signalling mechanism that determines the process of decision-making in response to DNA damage and involves the participation of multiple proteins. ATM is activated by DNA double-strand breaks (DSBs) through the Mre11–Rad50–Nbs1 (MRN) DNA repair complex, and orchestrates signalling cascades that initiate the DNA damage response. Cells lacking ATM are hypersensitive to insults, particularly genotoxic stress, induced through radiation or radiomimetic drugs. Here, we investigate the degree of ATM activation during time-dependent treatment with genotoxic agents and the effects of ATM on phospho-induction and localization of its downstream substrates. Additionally, we have demonstrated a new cell-cycle-independent mechanism of ATM gene regulation following ATM kinase inhibition with KU5593. Inhibition of ATM activity causes induction of ATM protein followed by oscillation and this mechanism is governed at the transcriptional level. Furthermore, this autoregulatory induction of ATM is also accompanied by a transient upregulation of p53, pATR and E2F1 levels. Since ATM inhibition is believed to sensitize cancer cells to genotoxic agents, this novel insight into the mechanism of ATM regulation might be useful for designing more precise strategies for modulation of ATM activity in cancer therapy.
Original languageEnglish
Pages (from-to)622-634
Number of pages13
JournalExperimental Biology and Medicine
Volume237
Issue number6
DOIs
Publication statusPublished - Jun 2012

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Ataxia Telangiectasia
Transcription
Pharmacology
DNA
Phosphotransferases
Ataxia Telangiectasia Mutated Proteins
Cells
Gene expression
DNA Damage
Repair
Decision making
Chemical activation
Modulation
Radiation
2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one
Inhibition (Psychology)
Substrates
Pharmaceutical Preparations
Proteins
Double-Stranded DNA Breaks

Cite this

Khalil, Hilal S. ; Tummala, Hemanth ; Hupp, Ted R. ; Zhelev, Nikolai. / Pharmacological inhibition of ATM by KU55933 stimulates ATM transcription. In: Experimental Biology and Medicine. 2012 ; Vol. 237, No. 6. pp. 622-634.
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Pharmacological inhibition of ATM by KU55933 stimulates ATM transcription. / Khalil, Hilal S.; Tummala, Hemanth; Hupp, Ted R.; Zhelev, Nikolai.

In: Experimental Biology and Medicine, Vol. 237, No. 6, 06.2012, p. 622-634.

Research output: Contribution to journalArticle

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