Laurence H. Kedes Professor Keck School of Medicine Institute for Genetic Medicine

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.