Publications by authors named "Michelle Demory"

3 Publications

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Epidermal growth factor receptor translocation to the mitochondria: regulation and effect.

J Biol Chem 2009 Dec 19;284(52):36592-36604. Epub 2009 Oct 19.

Department of Microbiology and the Cancer Center, University of Virginia, Charlottesville, Virginia 22908. Electronic address:

Co-overexpression of the epidermal growth factor (EGF) receptor (EGFR) and c-Src frequently occurs in human tumors and is linked to enhanced tumor growth. In experimental systems this synergistic growth requires EGF-dependent association of c-Src with the EGFR and phosphorylation of Tyr-845 of the receptor by c-Src. A search for signaling mediators of Tyr(P)-845 revealed that mitochondrial cytochrome c oxidase subunit II (CoxII) binds EGFR in a Tyr(P)-845- and EGF-dependent manner. In cells this association involves translocation of EGFR to the mitochondria, but regulation of this process is ill-defined. The current study demonstrates that c-Src translocates to the mitochondria with similar kinetics as EGFR and that the catalytic activity of EGFR and c-Src as well as endocytosis and a mitochondrial localization signal are required for these events. CoxII can be phosphorylated by EGFR and c-Src, and EGF stimulation reduces Cox activity and cellular ATP, an event that is dependent in large part on EGFR localized to the mitochondria. These findings suggest EGFR plays a novel role in modulating mitochondrial function via its association with, and modification of CoxII.
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December 2009

Phosphorylation of Y845 on the epidermal growth factor receptor mediates binding to the mitochondrial protein cytochrome c oxidase subunit II.

Mol Cell Biol 2004 Aug;24(16):7059-71

Department of Microbiology and Cancer Center, University of Virginia Health System, Charlottesville, VA 22908, USA.

When co-overexpressed, the epidermal growth factor receptor (EGFR) and c-Src cooperate to cause synergistic increases in EGF-induced DNA synthesis, soft agar colony growth, and tumor formation in nude mice. This synergy is dependent upon c-Src-mediated phosphorylation of a unique tyrosine on the EGFR, namely, tyrosine 845 (Y845). Phenylalanine substitution of Y845 (Y845F) was found to inhibit EGF-induced DNA synthesis without affecting the catalytic activity of the receptor or its ability to phosphorylate Shc or activate mitogen-activated protein kinase. These results suggest that synergism may occur through alternate signaling pathways mediated by phosphorylated Y845 (pY845). One such pathway involves the transcription factor Stat5b. Here we describe another pathway that involves cytochrome c oxidase subunit II (CoxII). CoxII was identified as a specific binding partner of a pY845-containing peptide in a phage display screen. EGF-dependent binding of CoxII to the wild type but not to the mutant Y845F-EGFR was confirmed by coimmunoprecipitation experiments. This association also required the kinase activity of c-Src. Confocal microscopy, as well as biochemical fractionation, indicated that the EGFR translocates to the mitochondria after EGF stimulation, where it colocalizes with CoxII. Such translocation required the catalytic activity of the receptor but not phosphorylation of Y845. However, ectopic expression of the Y845F-EGFR prevented the EGF from protecting MDA-MB-231 breast cancer cells from adriamycin-induced apoptosis, whereas two mutants of Stat5b, a dominant-interfering mutant (DNstat5b) and a tyrosine mutation at 699 (Y699F-Stat5b) did not. Taken together, these data suggest that, through the ability of EGFR to translocate to the mitochondria, the binding of proteins such as CoxII to pY845 on the EGFR may positively regulate survival pathways that contribute to oncogenesis.
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August 2004

Acute lower gastroenteric bleeding retrospective analysis (the ALGEBRA study): an analysis of the triage, management and outcomes of patients with acute lower gastrointestinal bleeding.

Am Surg 2003 Feb;69(2):145-9

Department of Surgery, Division of Colorectal Surgery, Washington Hospital Center, Medlantic Research Institute, Washington, DC 20010, USA.

Many algorithms have been developed for patients with acute lower gastrointestinal hemorrhage (ALGIH). Their clinical usefulness is not readily apparent. It is important first to observe patterns in admission, triage, and management to formulate hypotheses as to how outcomes might be affected. We reviewed patient charts with the diagnosis of gastrointestinal hemorrhage from June 1998 to January 2001. Patients with ALGIH were entered into a database. We defined patients as having ALGIH if presentation included melena or hematochezia. Patients with hematemesis, bloody nasogastric aspirate, or occult fecal blood were excluded. Observations were made on 420 patients. Seventy-six per cent of patients were admitted to the medical service. Lower endoscopy was the first diagnostic method in 33 per cent. Medical management comprised 52 per cent of first management strategies. Surgeons used angiography (3% vs 1%) or surgery (25% vs 5%) more than other services. Fourteen per cent of patients managed with endoscopy, 16 per cent medically, 17 per cent with surgery, and 67 per cent with interventional radiology required two or more subsequent packed red blood cell transfusions. Mean admission Acute Physiology and Chronic Health Evaluation II score was 9.2 whereas that for those with mortality was 13.5. We conclude that the construction of a database will allow for formation and testing of hypotheses in managing ALGIH.
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February 2003