Education:
BS 1961 Basic Med. Sciences- Stanford University, Stanford, CA
MD 1962 Medicine- Stanford University, Stanford, CA
Postdoctoral Research Fellowship:
1967-1969 Massachusettes Institute of Technology, Cambridge
Started at USC: 1988
Research Topics: Gene Regulation/Transcription, Cell Structure & Organization, Gene Therapy, Cardiovascular & Skeletal Muscle Diseases, Developmental Biology, Human/Mammalian Genetics
Research Description
We are interested in understanding the molecular mechanisms controlling tissue specific gene expression. We have been exploring and comparing the specialized functions of transcription in skeletal and cardiac muscle.
We have identified and are further characterizing gene products that interact with myogenic differentiation transcription factors (MyoD family, MEF2). These factors, such as pCAF, p300/CBP, and p160 members are ubiquitously expressed and provide physical links to the components of the general transcription machinery. These studies have illuminated the regulatory roles played by post-translational modifications, such as acetylation-deacetylation, on the activities of the transcription factor components.
While many of the same protein components make up the structural contractile elements of both skeletal and cardiac muscle cells, the modes of tissue specific regulation are far from identical. The Kedes lab has been investigating these differences and has discovered both positive and negative regulators of cardiac gene expression in neonatal and adult cardiomyocytes. We have identified two proteins whose genes are the major direct transcriptional targets of the Notch signaling pathway. These proteins, HERP1 and HERP2, in turn suppress downstream genes and modulate cell phenotype. The two genes are mutually exclusive in atrial and ventricular myocardium and we have developed evidence that they cross suppress each other's expression and suppress cardiac specific genes leading to accumulation of other chamber specific gene products.
Gene expression is grossly perturbed in various pathobiologoical processes involving the myocardium such as cardiomyopathy, myocardial infarction and preconditioning ischemia. Doxorubicin, a potent chemotherapeutic agent used to treat cancers including breast cancer and myelogenous leukemia, can cause a dose-limiting severe cardiomyopathy and congestive heart failure. Work in the Kedes lab has demonstrated that down-regulation of tissue specific cardiac genes is a central mechanism. The drug directly suppresses tissue specific transcription factors at the level of their own transcription and by accelerating the destruction of cellular co-factors (p300) at the protein level. In addition we have used microarray chip analysis to compare cardiac gene expression patterns in normal versus injured myocardium. Affymetrix and real-time PCR analyses have revealed a wide variety of unsuspected alterations in these patterns that has identified potentially causally-related new candidate gene categories.
Recent work has focused on the organization of actin filaments and the role of the actib capping protein, tropomodulin, in effecting filament structure. The discovery that this muscle filament protein binds with great affinity to non-muscle tropomyosins has us topostulate a novel organization of actin thin filaments (see figure) with at least one pair of non-muscle tropomyosins as the penultimate component of the thin filament then capped by tropomodulin.
Selected Publications
Caulfield T, McGuire AL, Cho M, Buchanan JA, Burgess MM, Danilczyk U, Diaz CM, Fryer-Edwards K, Green SK, Hodosh MA, Juengst ET, Kaye J, Kedes L, Knoppers BM, Lemmens T, Meslin EM, Murphy J, Nussbaum RL, Otlowski M, Pullman D, Ray PN, Sugarman J, Timmons M. - Research ethics recommendations for whole-genome research: consensus statement. - PLoS Biol [ 2008 ] Mar 25;6(3):e73 . PubMed
Kedes L. - Genomics prize--the X PRIZE Foundation. Interview by Vicki Glaser. - Rejuvenation Res [ 2007 ] Jun;10(2):237-42 . PubMed
Sakoda T, Kasahara N, Kedes L, Ohyanagi M. - Lentiviral vector-mediated gene transfer to endotherial cells compared with adenoviral and retroviral vectors. - Prep Biochem Biotechnol [ 2007 ] 37(1):1-11 . PubMed
Tanaka T, Nishimura D, Wu RC, Amano M, Iso T, Kedes L, Nishida H, Kaibuchi K, Hamamori Y. - Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase. - J Biol Chem [ 2006 ] Jun 2;281(22):15320-9 . PubMed
Kong KY, Kedes L. - Leucine 135 of tropomodulin-1 regulates its association with tropomyosin, its cellular localization, and the integrity of sarcomeres. - J Biol Chem [ 2006 ] Apr 7;281(14):9589-99 . PubMed
Doi H, Iso T, Yamazaki M, Akiyama H, Kanai H, Sato H, Kawai-Kowase K, Tanaka T, Maeno T, Okamoto E, Arai M, Kedes L, Kurabayashi M. - HERP1 inhibits myocardin-induced vascular smooth muscle cell differentiation by interfering with SRF binding to CArG box. - Arterioscler Thromb Vasc Biol [ 2005 ] Nov;25(11):2328-34 . PubMed
Dow J, Simkhovich BZ, Kedes L, Kloner RA. - Washout of transplanted cells from the heart: a potential new hurdle for cell transplantation therapy. - Cardiovasc Res [ 2005 ] Aug 1;67(2):301-7 . PubMed
Poizat C, Puri PL, Bai Y, Kedes L. - Phosphorylation-dependent degradation of p300 by doxorubicin-activated p38 mitogen-activated protein kinase in cardiac cells. - Mol Cell Biol [ 2005 ] Apr;25(7):2673-87 . PubMed
Wu HY, Hamamori Y, Xu J, Chang SC, Saluna T, Chang MF, O'Malley BW, Kedes L. - Nuclear hormone receptor coregulator GRIP1 suppresses, whereas SRC1A and p/CIP coactivate, by domain-specific binding of MyoD. - J Biol Chem [ 2005 ] Feb 4;280(5):3129-37 . PubMed
Rentsendorj A, Agadjanian H, Chen X, Cirivello M, Macveigh M, Kedes L, Hamm-Alvarez S, Medina-Kauwe LK. - The Ad5 fiber mediates nonviral gene transfer in the absence of the whole virus, utilizing a novel cell entry pathway. - Gene Ther [ 2005 ] Feb;12(3):225-37 . PubMed
