The tumor-promoting functions of Ataxia-telangiectasia mutated (ATM) in cancer cells

textAtaxia-telangiectasia mutated (ATM) protein kinase regulates the DNA damage response (DDR) and is associated with cancer suppression by protecting cells from DNA double-strand breaks (DSBs). However, how ATM functions outside of DSB signaling is less clearly understood. Here, we report a new cancer-promoting role for ATM in stimulating cell migration and invasion independently of DSB signaling or induction. We used two highly metastatic human breast cancer cell lines to corroborate that ATM is required for cell migration and invasion. Microarray analysis of cells depleted for ATM identified interleukin-8 (IL-8) as a target since the exogenous addition of IL-8 rescued migration and invasion defects in ATM-deficient cells. Finally, ATM depletion in human cancer cells reduced lung metastasis in a mouse xenograft model. These findings shed light on tumor-promoting functions of ATM. Therefore, in addition to its canonical roles in tumor suppression, ATM promotes tumor progression as well.Cellular and Molecular Biolog

Replication stress and chromatin context link ATM activation to a role in DNA replication

ATM-mediated signaling in response to DNA damage is a barrier to tumorigenesis. Here we asked whether replication stress could also contribute to ATM signaling. We demonstrate that, in the absence of DNA damage, ATM responds to replication stress in a hypoxia-induced heterochromatin-like context. In certain hypoxic conditions, replication stress occurs in the absence of detectable DNA damage. Hypoxia also induces H3K9me3, a histone modification associated with gene repression and heterochromatin. Hypoxia-induced replication stress together with increased H3K9me3 leads to ATM activation. Importantly, ATM prevents the accumulation of DNA damage in hypoxia. Most significantly, we describe a stress-specific role for ATM in maintaining DNA replication rates in a background of increased H3K9me3. Furthermore, the ATM-mediated response to oncogene-induced replication stress is enhanced in hypoxic conditions. Together, these data indicate that hypoxia plays a critical role in the activation of the DNA damage response, therefore contributing to this barrier to tumorigenesis

Performance and Buffering Requirements of Internet Protocols over ATM ABR and UBR Services

The Asynchronous Transfer Mode (ATM) networks are quickly being adopted as backbones over various parts of the Internet. This paper analyzes the performance of TCP/IP protocols over ATM network's Available Bit Rate (ABR) and Unspecified Bit Rate (UBR) services. It is shown that ABR pushes congestion to the edges of the ATM network while UBR leaves it inside the ATM portion.Comment: IEEE Communications Magazine, Vol 36, no 6, pp152-15

Targeting ATM pathway for therapeutic intervention in cancer

The Ataxia Telangiectasia Mutated gene encodes the ATM protein, a key element in the DNA damage response (DDR) signalling pathway responsible for maintaining genomic integrity within the cell. The ATM protein belongs to a family of large protein kinases containing the phosphatidylinositol-3 catalytic domain, including ATM, ATR and PI3K. ATM provides the crucial link between DNA damage, cell cycle progression and cell death by first sensing double stranded DNA breaks and subsequently phosphorylating and activating other downstream proteins functioning in DNA damage repair, cell cycle arrest and apoptotic pathways,. Mammalian cells are constantly challenged by genotoxic agents from a variety of sources and therefore require a robust sensing and repair mechanism to maintain DNA integrity or activate alternative cell fate pathways. This review covers the role of ATM in DDR signalling and describes the interaction of the ATM kinase with other proteins in order to fulfil its various functions. Special emphasis is given to how the growing knowledge of the DDR can help identify drug targets for cancer therapy, thus providing a rationale for exploiting the ATM pathway in anticancer drug development. Moreover, we discuss how a network modelling approach can be used to identify and characterise ATM inhibitors and predict their therapeutic potential

Atrophy, oxidative switching and ultrastructural defects in skeletal muscle of the ataxia telangiectasia mouse model

Ataxia telangiectasia is a rare, multi system disease caused by ATM kinase deficiency. Atm-knockout mice recapitulate premature aging, immunodeficiency, cancer predisposition, growth retardation and motor defects, but not cerebellar neurodegeneration and ataxia. We explored whether Atm loss is responsible for skeletal muscle defects by investigating myofiber morphology, oxidative/glycolytic activity, myocyte ultrastructural architecture and neuromuscular junctions. Atm-knockout mice showed reduced muscle and fiber size. Atrophy, protein synthesis impairment and a switch from glycolytic to oxidative fibers were detected, along with an increase of in expression of slow and fast myosin types (Myh7, and Myh2 and Myh4, respectively) in tibialis anterior and solei muscles isolated from Atm-knockout mice. Transmission electron microscopy of tibialis anterior revealed misalignments of Z-lines and sarcomeres and mitochondria abnormalities that were associated with an increase in reactive oxygen species. Moreover, neuromuscular junctions appeared larger and more complex than those in Atm wild-type mice, but with preserved presynaptic terminals. In conclusion, we report for the first time that Atm-knockout mice have clear morphological skeletal muscle defects that will be relevant for the investigation of the oxidative stress response, motor alteration and the interplay with peripheral nervous system in ataxia telangiectasia

Air Traffic Management Safety Challenges

The primary goal of the Air Traffic Management (ATM) system is to control accident risk. ATM safety has improved over the decades for many reasons, from better equipment to additional safety defences. But ATM safety targets, improving on current performance, are now extremely demanding. Safety analysts and aviation decision-makers have to make safety assessments based on statistically incomplete evidence. If future risks cannot be estimated with precision, then how is safety to be assured with traffic growth and operational/technical changes? What are the design implications for the USA’s ‘Next Generation Air Transportation System’ (NextGen) and Europe’s Single European Sky ATM Research Programme (SESAR)? ATM accident precursors arise from (eg) pilot/controller workload, miscommunication, and lack of upto- date information. Can these accident precursors confidently be ‘designed out’ by (eg) better system knowledge across ATM participants, automatic safety checks, and machine rather than voice communication? Future potentially hazardous situations could be as ‘messy’ in system terms as the Überlingen mid-air collision. Are ATM safety regulation policies fit for purpose: is it more and more difficult to innovate, to introduce new technologies and novel operational concepts? Must regulators be more active, eg more inspections and monitoring of real operational and organisational practices

The ATM Reforms - New Evidence from Survey and Market Data

Following the introduction of direct charging in March 2009, ATM pricing has become more transparent and flexible. Cardholders continue to respond to the clearer price signals by changing their cash withdrawal behaviour to avoid paying direct charges, and newly available data indicate that behaviour varies across age groups and geographic locations. For the small proportion of transactions that do incur a direct charge, flexibility in ATM pricing has led to a distinct pattern in these charges across different types of ATM locations. Variations in business models between ATM owners mean that most consumers have access to a large number of ATMs on which they pay no direct charge, while it remains possible for ATMs to be profitably deployed in high-cost or low-volume locations.ATMs; ATM reforms; ATM fees; foreign fees; foreign ATMs; direct charging; ATM surcharging; interchange fees; ATM Access Regime; ATM Deployment; payments reform; consumer use study; payment patterns; consumer behaviour

Survey of traffic control schemes and error control schemes for ATM networks

Among the techniques proposed for B-ISDN transfer mode, ATM concept is considered to be the most promising transfer technique because of its flexibility and efficiency. This paper surveys and reviews a number of topics related to ATM networks. Those topics cover congestion control, provision of multiple classes of traffic, and error control. Due to the nature of ATM networks, those issues are far more challenging than in conventional networks. Sorne of the more promising solutions to those issues are surveyed, and the corresponding results on performance are summarized. Future research problems in ATM protocol aspect are also presented