Deborah L. Johnson Professor Biochemistry & Molecular Biology Keck School of Medicine

Education:
BS 1976 Biochemistry - Albright College, Pennsylvania
PhD 1980 Chemistry - Georgetown, Washington D.C.

Postdoctoral Research Fellowship:
1981 - 1985 Yale University, Conneticut

Started at USC: 1985

Research Topics: Gene Regulation/Transcription, Cancer Cell Biology, Signal Transduction, Cell Cycle, Growth & Proliferation, Cancer Genetics

Research Description

Role of the central transcription initiation factor, TBP, in oncogenesis

We have made the discovery that the levels of the central transcription factor, TATA binding protein (TBP), are elevated in cells expressing oncogenic Ras and that increased expression of TBP selectively regulates cellular gene expression. We have further demonstrated that enhanced expression of TBP induces anchorage-independent growth and tumor formation in mice, and that specifically abrogating Ras-induced increases in TBP inhibits Ras-transforming activity. These results support the hypothesis that deregulation of an apparently “general” transcription initiation factor plays a key role in cellular transformation. One of our goals is to identify the extracellular cues and signaling pathways that regulate TBP expression, and to determine the phenotypic consequences resulting from changes in the cellular concentrations of TBP mediated by these signaling events. To this end, we are currently examining the potential for members of the epidermal growth factor receptor family to regulate TBP expression. Since the activation of these EGFRs and their downstream signaling targets, such as the JNKs, have been shown to affect cell proliferation and the oncogenic state of cells, we are determining whether alterations in cellular TBP concentrations are critical for mediating changes in these cellular processes. A second goal is to identify TBP-mediated changes in gene expression that are required to mediate changes in these cellular processes. We have found that enhanced expression of RNA polymerase (pol) III genes, and increased levels of tRNAs and 5S rRNAs, are required for TBP-mediated transformation. Microarray analysis has further revealed that small changes in cellular TBP levels alter the expression of genes involved in cytoskeletal reorganization and angiogenesis. Thus, our current studies aim to investigate the role of TBP in cell migration and angiogenesis. Our third goal is to determine whether enhanced expression of TBP plays a role in the development of human cancer. To this end, we are comparing the relative levels of TBP expression in normal human colon and tumor tissue.

Regulation of RNA pol I and pol III transcription by the tumor suppressor, PTEN

Our overall goal is to identify the specific downstream gene targets of PTEN that are important in its function as a tumor suppressor, and the molecular consequences resulting from its loss in human cancer. Our hypothesis is that the tumor suppressor PTEN mediates repression of RNA polymerase (pol) I- and III-dependent transcription, responsible for the synthesis of rRNAs and tRNAs. As these RNAs are major determinants of the biosynthetic capacity of cells, their repression by PTEN may be fundamental to its tumor suppressing function. Thus, the deregulation of these genes would serve to enhance the translational capacity of cells required to promote cellular growth, proliferation and transformation. We have shown that loss of PTEN in cells, and the activation of PI3 kinase signaling, leads to induction of these genes. We are now identifying the specific downstream signaling molecules and the transcription factors that are targeted by PTEN and these pathways. Our studies so far support the idea that PTEN represses RNA pol I transcription by disrupting the formation of the SL1 transcription factor complex. Further defining the key cellular targets mediated by PTEN will provide new information for the design of novel therapeutic agents that inhibit the activation of RNA pol I and III transcription, and serve to abrogate cancer progression.