Ataxia Telangiectasia Mutated in Glucose Transport

Ataxia Telangiectasia Mutated in Glucose Transport A role for ataxia telangiectasia mutated in insulin-independent stimulation of glucose transport Abstract Literature reports suggest that ataxia telangiectasia mutated (ATM) can activate the AMP-activated protein kinase (AMPK), a protein that can stimulate glucose transport in skeletal muscle. We hypothesized that 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, would increase glucose transport in mouse extensor digitorum longus (EDL) muscles in an ATM-dependent manner. AICAR-stimulated glucose transport was prevented by the ATM inhibitor KU-55933 and in ATM-deficient (ATM-/-) muscle despite normal stimulation of AMPK phosphorylation. S231 of TBC1D1 matches the sequence motif of ATM substrates, and phosphorylation of this site is known to inhibit TBC1D1 and lead to increased glucose transport. Accordingly, we assessed TBC1D1 phosphorylation and found that AICAR-stimulated phosphorylation of TBC1D1 at S231did not occurin ATM-/- muscle. However, activation of ATM without activation of AMPK was insufficient to increase TBC1D1 phosphorylation.The data suggest that ATM plays a role in AICAR stimulated glucose transport downstream of AMPK. Keywords: AMP-activated protein kinase; ataxia telangiectasia mutated; TBC1D1; AICAR; glucose transport; skeletal muscle Introduction The serine-threonine kinase ataxia telangiectasia mutated (ATM) appears to play a role in glucose homeostasis. For example, recent genome-wide association studies have found that genetic variations near the ATM gene are related to glycemic responses to metformin [1, 2], a commonly-prescribed drug for blood glucose control. While the mechanism for metformin’s effect on blood glucose levels is under debate [3-6], it is known that metformin acutely stimulates glucose transport into skeletal muscle concomitant with activation of the AMP-activated protein kinase (AMPK) [7]. Activation of AMPK is sufficient to stimulate insulin-independent glucose transport into skeletal muscle [8, 9]. Intriguingly, ATM dependence has been reported for activation of AMPK in response to DNA damage or insulin-like growth factor 1 in HeLa cells and fibroblasts, exposure of lung cancer cells to ionizing radiation,exposure of lymphoblaststo H 2 O 2 , or treatment of HeLa cells and mouse embryonic fibroblasts with the adenosine analog AICAR [10-14]. Despite these suggestive data on the role of ATM upstream of AMPK, the potential role of ATM in AMPK-dependent stimulation of glucose transport has not previously been investigated in skeletal muscle, the predominant whole-body storage depot for glucose. Accordingly, the purpose of this study was to test the hypothesis that glucose uptake stimulated by the AMPK activator AICAR would be dependent on ATM in skeletal muscle. Methods Materials Antibodies against TBC1D1, AMPK, phosphorylated AMPKÃŽ ± T172 (P-AMPK), and phosphorylated ATM S1981 (P-ATM) were purchased from Cell Signaling Technology (Beverly, MA, USA). Antibodies aga inst phosphorylated TBC1D1 (P-TBC1D1) S237 (S231 in mouse) were purchased from EMD Millipore Corporation (Billerica, MA, USA). Antibodies against tubulin and ATM were obtained from Sigma-Aldrich Corporation (St. Louis, MO, USA). Horseradish peroxidase-conjugated secondary antibodies were obtained from Pierce Biotechnology (Rockford, IL, USA). The ATM inhibitor KU-55933 was a generous gift from Dr. Graeme Smith (KuDOSPhramaceuticals, Cambridge, UK). The AMPK inhibitor Compound C was provided by Merck & Co., Inc. (Rahway, NJ, USA). Doxorubicin was purchased from Sigma-Aldrich Corporation. Radiolabeled 2-deoxyglucose and mannitol were purchased from American Radiolabeled Chemicals, Inc. (St. Louis, MO, USA).

Week 3 Assignment Essay Example | Topics and Well Written Essays - 500 words - 1

Week 3 Assignment - Essay Example The book ‘Global issues in intellectual property law’ is a section of the GLOBAL ISSUES SERIES. Every book in the series has materials designed to assist the introduction of transnational, international, and comparative legal issues into courses of some schools. The aim of the series is to guarantee that every student has an adequate familiarity with the effect of non-domestic basis of law, and the increasing potential for transnational legal disputes and transactions, to work in this era of increasing globalization. Additionally, introduction of transnational, international and comparative law information can enhance a student’s comprehension of domestic law. The book is very important to this paper since it offers additional information pertaining to domestic laws on intellectual property. The book provides information on current issues in regard to intellectual property. Hansen, S., & VanFleet, J. (2003). Traditional Knowedge and Intellectual Property: A Handbook on Issues and Options for Traditional Knowledge Holders in Protecting their Intellectual Property and Maintaining Biological

American Law Enforcement - Ethical Dillemma Essay

American Law Enforcement - Ethical Dillemma - Essay Example Police ranks often pull together to support their own and when that does not work, the community will justify their actions by not holding them responsible for the outcomes of bad decision making. The ethics within the police rank appears to be teleological, supporting the concept of the means justifying the ends, despite all Constitutional efforts to dissuade this type of thinking. In a world that is becoming ever increasingly violent the service that is entered into by the police should reflect a higher standard of responsibility instead of a shield that protects them from the outcomes of their poor decision making processes. Incidents Death and Justification In the year 2000 Shannon Smith, a mentally disabled man of 27 who often forgot to pay for the gas he would pump into his Cadillac. The $15 dollars in gas was not the first that he had forgotten to pay, but he would remember and go back, or his father would take care of the bill for him when called. On this particular occasion, however, the clerk called the police and a slow pace pursuit began chasing the mentally disabled man across jurisdictions. ... Gabor was later charged with his murder (Reynolds, 2001). Despite evidence that Gabor had used his nightstick to pound on the car window and to kick at the car, he was acquitted of the charges. Smith’s family received $675,000 in a wrongful death settlement against Gabor from the police department who settled on Gabor’s behalf (Reynolds, 2002). On August 31st of this year Michael Vincent Allen was shot 41 times after a high speed chase that included a bashed in front end to a police vehicle. Police contend that at the end of a cul de sac Allen tried to make a u-turn which ended in the damage to the front of the police car, but witnesses contradicted that version and stated that it was the police car that rammed into Allen’s vehicle. The officer’s name, that has yet to be released, stood with his fellow officers and fired 41 times at the suspect while the other officers did not fire off a single shot (Peterson, 2012). The initial police reports supported th e officer through police accounts, but a wider investigation showed that he was aggressive and that he was the only one shooting is suspicious. Officer Mathew Jacob Marin, who has been a police officer for five years, shot and killed a man with only one arm and one leg in a wheelchair when he was cornered by the man who was waving around a metal object which turned out to be a pen. Marin was involved in a previous shooting death during his career when in 2009 he shot a suspect who was stabbing his neighbor and refused to drop the knife when confronted. In the same year, a poll taken by the Chicago Tribune found that 59% of police officers never fire their gun during their career. While the first incident seems justifiable for Marin,