Dr. David L. Levens, Head, Gene Regulation Section
Building 10, Room 2S235C
To learn more, visit Dr. Leven's CCR Web site.
Gene Regulation Section
Laboratory of Pathology, CCR
National Cancer Institute
9000 Rockville Pike
Building 10, Room 2N106
Bethesda, MD 20892
The Gene Regulation Section, Laboratory of Pathology, CCR, NCI studies the regulation of the transcription of the human c-myc proto-oncogene. The disregulation of this gene is implicated in the pathogenesis of a variety of human neoplasms. As a key regulator of cell growth and apoptosis, even minor perturbation of c-myc levels disturb the timing and progression of cell growth, the cell cycle, and proliferation. Despite intense and prolonged effort in many groups, the rules governing c-myc regulation have not been fully exposed. No model system including transient expression, stable transfection (either genomic or episomal) or transgenic animals has succeeded in conferring proper physiological regulation upon an exogenously introduced c-myc. Therefore either principle components or processes are missing or defective in these model systems. In addition to conventional transcription factors, the c-myc promoter binds multiple sequence specific and conformation sensitive DNA binding proteins, several of these were discovered and characterized in our group (FBPs 1-3, FIR, and hnRNPK ). The focus of the section since discovering these factors has been to elucidate the roles of these unusual proteins in the regulation of c-myc, FBP activation and FIR repression have been shown to operate through TFIIH and to delay or hasten promoter escape by paused RNA polymerase. Operation of the FBP-FIR-TFIIH system is defective in Xeroderma pigmentosum B and D, bearing mutated TFIIH subunits. Ongoing studies will relate this system to the physiological and biochemical processes and events that demand participation by these sequence and conformation sensitive nucleic acid binding proteins and to define the physiological and biochemical constraints demanding their participation.
- Analysis of the far upstream element (FUSE) binding protein (FBP) and its role in c-myc regulation.
- Investigation of the biological, biophysical and mechanical processes governing the generation and transmission of torsional stress in DNA and consequent changes in DNA conformation.
- Elucidation of the role and mechanism of TFIIH in the intergration of transcriptional signals during early stages of the transcription cycle.
- Analysis of the FBP Interacting Repressor (FIR) and its role in c-myc regulation and transcriptional repression.
- Identification of additional target genes and cis-elements of FBP and FIR. Role of FBP and FIR in the regulation of cell growth, proliferation and the cell-cycle.
- Structural studies of FBP-FUSE and FBP-FIR complexes.
- Characterization of the role of hnRNPK in the transcriptional control of c-myc and coupling of hnRNPK DNA binding activity with DNA topology. Structural studies of hnRNPK with the CT-element of c-myc.
- Characterization of a biological process discovered in our group which marks genes during metaphase, when transcription shuts down, scheduled to be re-expressed following mitosis. This process involves modulation of DNA conformation