The mTOR pathway negatively controls ATM by up-regulating miRNAs

Abstract

The ataxia telangiectasia mutated (ATM) checkpoint is the central surveillance system that maintains genome integrity. We found that in the context of childhood sarcoma, mammalian target of rapamycin (mTOR) signaling suppresses ATM by up-regulating miRNAs targeting ATM . Pharmacological inhibition or genetic down-regulation of the mTOR pathway resulted in increase of ATM mRNA and protein both in mouse sarcoma xenografts and cultured cells. mTOR Complex 1 (mTORC1) suppresses ATM via S6K1/2 signaling pathways. microRNA-18a and microRNA-421, both of which target ATM, are positively controlled by mTOR signaling. Our findings have identified a negative feedback loop for the signaling between ATM and mTOR pathways and suggest that oncogenic growth signals may promote tumorigenesis by dampening the ATM checkpoint.

Having Pancreatic Cancer with Tumoral Loss of ATM and Normal TP53 Protein Expression Is Associated with a Poorer Prognosis

“…Somatic ATM inactivation is generally by intragenic mutation according to the literature, although other mechanisms are possible (23). Recent studies have identified other mechanisms of ATM downregulation via microRNAs and the mTOR pathway (24). In most cases, ATM mutations are nonsense mutations, giving rise to truncated ATM protein, although other types of mutations have been reported, including missense mutations or in-frame deletions producing catalytically inactive ATM proteins (9).…”

Glutaminolysis and autophagy in cancer

“…In addition to that, the activation of MTORC1 by glutaminolysis also inhibits autophagy and ATM, a protein involved in the DNA damage response (DDR). 40,[49][50][51] Hence, a high rate of glutaminolysis promotes the progression of cancer at early stages, not only stimulating cell growth through the MTORC1 pathway, but also impairing the proper removal of damaged proteins and organelles through the inhibition of autophagy and through ATM-dependent DDR, which eventually would contribute to the initiation of cancer.…”

Radiosensitivity of Human Breast Cancer Cell Lines Expressing the Breast Tumor Kinase (Brk)

“…However, this is a pertinent enquiry vis-à-vis the potential modulation of ATM activity via Brk. Brk over-expression has previously been linked to enhanced ErbB signalling [8,23,14], a pathway with known links to radiation sensitivity [23]. Moreover it has been recently demonstrated that enhanced mTOR signalling in the context of childhood sarcoma mediated down-regulation of ATM by microRNA [22].…”

“…PI3-K/ AKT/mTOR is considered as a potential therapeutic target in breast cancer [13]. Moreover, elevated mTOR signalling is known to suppress the ataxia telangiectasia mutated protein (ATM) expression by inducing microRNAs targeting ATM for destruction [14]. ATM is a key cell cycle regulator and mutational inactivation leads to extreme cellular and clinical sensitivity to radiation [15].…”