Search Results (2)

ATM is one of the principal players of the DNA damage response. This protein exerts its role in DNA repair during cell cycle replication, oxidative stress, and DNA damage from endogenous events or exogenous agents. When is activated, ATM phosphorylates multiple substrates that participate in DNA repair, through its phosphoinositide 3-kinase like domain at the 3′end of the protein. The absence of ATM is the cause of a rare autosomal recessive disorder called Ataxia Telangiectasia characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitivity. There is a correlation between the severity of the phenotype and the mutations, depending on the residual activity of the protein. The analysis of patient mutations and mouse models revealed that the presence of inactive ATM, named ATM kinase-dead, is more cancer prone and lethal than its absence. ATM mutations fall into the whole gene sequence, and it is very difficult to predict the resulting effects, except for some frequent mutations. In this regard, is necessary to characterize the mutated protein to assess if it is stable and maintains some residual kinase activity. Moreover, the whole-genome sequencing of cancer patients with somatic or germline mutations has highlighted a high percentage of ATM mutations in the phosphoinositide 3-kinase domain, mostly in cancer cells resistant to classical therapy. The relevant differences between the complete absence of ATM and the presence of the inactive form in in vitro and in vivo models need to be explored in more detail to predict cancer predisposition of A-T patients and to discover new therapies for ATM-associated cancer cells. In this review, we summarize the multiple discoveries from humans and mouse models on ATM mutations, focusing into the inactive versus null ATM. Full article

Ataxia-telegiectasia mutated (ATM), phosphatase and tensin homolog (PTEN), and p85α are key tumour suppressors. Whether ATM regulates PTEN expression and influence platinum sensitivity is unknown. We generated ATM knockdowns (KD) and CRISPR knock outs (KO) in glioblastoma (LN18, LN229) and ovarian cancer cells (OVCAR3, OVCAR4). Doxycycline inducible PTEN expression was generated in LN18 and LN229 cells. Transient KD of p85α, CK2, and XIAP was accomplished using siRNAs. Stable p85α knock-in was isolated in LN18 cells. Molecular biology assays included proteasome activity assays, PCR, flow cytometry analysis (cell cycle, double strand break accumulation, apoptosis), immunofluorescence, co-immunoprecipitation, clonogenic, invasion, migration, and 3D neurosphere assays. The clinicopathological significance of ATM, PTEN, p85α, and XIAP (X-linked inhibitor of apoptosis protein) was evaluated in 525 human ovarian cancers using immunohistochemistry. ATM regulated PTEN is p85α dependant. ATM also controls CK2α level which in turn phosphorylates and stabilizes PTEN. In addition, p85α physically interacts with CK2α and protects CK2α from ATM regulated degradation. ATM deficiency resulted in accumulation of XIAP/p-XIAP levels which ubiquitinated PTEN and CK2α thereby directing them to degradation. ATM depletion in the context of p85α deficiency impaired cancer cell migration and invasion reduced 3D-neurosphere formation and increased toxicity to cisplatin chemotherapy. Increased sensitivity to platinum was associated with DNA double strand breaks accumulation, cell cycle arrest, and induction of autophagy. In ovarian cancer patients, ATM, PTEN, p85α, and XIAP protein levels predicted better progression free survival after platinum therapy. We unravel a previously unknown function of ATM in the regulation of PTEN throμgh XIAP mediated proteasome degradation. Full article