UPHS News: Penn Researchers Discover Second Molecular = Pathway that Promotes Cell Survival During Low Oxygen Conditions

From: Subject: UPHS News: Penn Researchers Discover Second Molecular Pathway that Promotes Cell Survival During Low Oxygen Conditions Date: Wed, 17 May 2006 13:59:59 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C679BA.2F9BB790" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.2869 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C679BA.2F9BB790 Content-Type: text/html; charset="utf-8" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.uphs.upenn.edu/news/News_Releases/feb06/O2cellsrv.htm =EF=BB=BF UPHS News: Penn Researchers Discover Second Molecular = Pathway that Promotes Cell Survival During Low Oxygen Conditions

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M. = Celeste=20 Simon, PhD

M. = Celeste=20 Simon, PhD at the Abramson Family Cancer Research=20 Institute

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	NEWS=20 RELEASE =20 FEBRUARY 16, 2006
	Penn Researchers Discover = Second=20 Molecular Pathway that Promotes Cell Survival During Low = Oxygen=20 Conditions
	Findings Give Clues to = Cancer,=20 Cardiovascular Disease Physiology
		(Philadelphia, PA) - Researchers at the = University of=20 Pennsylvania School of Medicine have identified a = second=20 molecular pathway that promotes cell survival in low-oxygen=20 conditions. By teasing apart the details of cellular = adaptation=20 during oxygen deprivation, or hypoxia, the researchers hope = to gain=20 a better understanding of the abnormal hypoxic environments = that are=20 characteristic of many diseases, including solid-tumor = cancers and=20 stroke. Oxygen sensing, the ability of a cell to = gauge the=20 oxygen concentrations in its environment and to protect = itself=20 through internal regulation, is a fundamental process in = most=20 species of animals that depend entirely on oxygen to = maintain=20 cellular function. There are multiple, oxygen-dependent = pathways in=20 the cell that are regulated by changes in oxygen = levels. By starving human = cells of oxygen,=20 Celeste Simon, PhD, Professor of Cell and=20 Developmental Biology at Penn and a Howard Hughes Medical = Institute=20 (HHMI) Investigator, and colleagues discovered an = oxygen-sensitive=20 cellular pathway that leads to a decrease in protein = synthesis. This=20 finding is the second hypoxic cellular pathway to be = identified by=20 this research team. Simon, who is also a member of = Penn=E2=80=99s=20 Abramson Cancer Center, and colleagues = report their=20 most recent findings in the February issue of Molecular=20 Cell. In order to promote cellular adaptations = to=20 hypoxia, the cell must first recognize the presence of a = low-oxygen=20 environment. Previous genetic studies from Simon=E2=80=99s = laboratory helped=20 to establish that the mitochondria-the energy center of the=20 cell-play a major role in oxygen sensing. Like an alarm,=20 mitochondria alert the cells when oxygen levels fall too = low,=20 resulting in hypoxic cells activating a protein called=20 hypoxia-inducible factor (HIF). HIF, in turn, signals for=20 physiological changes in nearby tissue that serve to protect = oxygen-deprived cells. These changes include an increase in = the=20 number of red blood cells and blood vessels, the dilation of = vessels, and changes in cell motility. =E2=80=9CThese = physiological=20 changes make biological sense,=E2=80=9D explains Simon. = =E2=80=9CThe changes allow=20 the affected cell, or tissue, to withstand the stress of low = oxygen.=20 Changes in the blood cells and vasculature enhance the = ability of=20 the blood stream to carry oxygen to the effected = regions.=E2=80=9D In=20 their most recent studies, Simon=E2=80=99s group revealed = the ability of=20 cells to adapt to low-oxygen concentrations through a second = molecular pathway. In order to protect itself during hypoxic = conditions, a cell will conserve energy by greatly reducing = protein=20 synthesis. By exposing human cells to low-oxygen conditions, = the=20 researchers observed the inactivation of mTOR, a central = regulator=20 of global protein synthesis. Further genetic testing = revealed that=20 the mTOR pathway operates independent of the HIF=20 pathway. Though paradoxical, Simon=E2=80=99s findings = suggest that=20 the HIF pathway leads to the activation and translation of = nearly=20 200 target genes essential to the cell=E2=80=99s protective = physiological=20 changes, while the second and most recently discovered = pathway-the=20 mTOR pathway-inhibits protein synthesis. =E2=80=9CThe cell = needs to take=20 what energy it has to redirect to the molecular response = that=20 results in the necessary physiological changes,=E2=80=9D = Simon=20 suggests. =E2=80=9CThere is something about the = messenger RNAs=20 present in the HIF pathway that allows them to escape = inhibition of=20 global protein synthesis,=E2=80=9D Simon notes. She believes = that the=20 directions for these mRNAs to move forward and make protein, = while=20 many are left behind, lies in the genetic makeup of mRNA. = Her lab is=20 currently working to identify these molecular=20 directions. Although hypoxic conditions exist = throughout=20 early embryonic development, the presence of hypoxic = environments in=20 adult tissue is often a response to disease. As Simon = explains, =E2=80=9CA=20 lot of the major Western world scourges involve a decrease = in oxygen=20 availability that falls below the threshold that cells need = to=20 remain healthy and carry out their functions.=E2=80=9D = Hypoxia is a=20 prominent component of solid tumors, myocardial infarctions, = stroke,=20 diabetic retinopathy, inflammation, and = atherosclerosis. In=20 addition to hypoxia, solid cancer tumors are comprised of = abnormal=20 cells and convoluted blood vessels, which allow the tumors = to resist=20 chemotherapy and radiation treatments. New treatments for = cancer are=20 now aiming to turn off HIF and mTOR activity, halting the = ability of=20 the cell to signal its low-oxygen alert system and undergo = protein=20 synthesis. =E2=80=9CIf we are able to create a = treatment for tumors=20 by inactivating the factor that is promoting cell survival = and tumor=20 cell motility - a key regulator of tumor metastasis - we may = have=20 another option to treat solid tumors,=E2=80=9D notes Simon. = Study=20 co-authors are Liping Liu, Timothy P. Cash, Russell G. = Jones, Brian=20 Keith and Craig B. Thompson, all from the Abramson Family = Cancer=20 Research Institute (AFCRI). The research was funded by the = National=20 Institutes of Health, HHMI, and AFCRI. ### PENN Medicine is a $2.7 billion = enterprise=20 dedicated to the related missions of medical education, = biomedical=20 research, and high-quality patient care. PENN Medicine = consists of=20 the University of Pennsylvania School of Medicine (founded = in 1765=20 as the nation's first medical school) and the University of=20 Pennsylvania Health System. Penn=E2=80=99s School of Medicine is ranked #2 in the = nation for=20 receipt of NIH research funds; and ranked #4 in the nation = in U.S.=20 News & World Report=E2=80=99s most recent ranking of top = research-oriented medical schools. Supporting 1,400 fulltime = faculty=20 and 700 students, the School of Medicine is recognized = worldwide for=20 its superior education and training of the next generation = of=20 physician-scientists and leaders of academic = medicine. The University of Pennsylvania Health System = comprises: its=20 flagship hospital, the Hospital of the University of = Pennsylvania,=20 consistently rated one of the nation=E2=80=99s = =E2=80=9CHonor Roll=E2=80=9D hospitals by=20 U.S. News & World Report; Pennsylvania Hospital, the = nation's=20 first hospital; Penn Presbyterian Medical Center; a faculty = practice=20 plan; a primary-care provider network; two multispecialty = satellite=20 facilities; and home health care and hospice.

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The University of = Pennsylvania Health=20 System, Philadelphia, PA 1-800-789-PENN =C2=A9 2006, The = Trustees of the=20 University of Pennsylvania

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