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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.
Research
Topics
- 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
Recent Publications
Lab
members
This section contains links to lab members' research and professional
pages.
The
Levens lab can be reached at:
Building
10 Room 2N105
National Institutes of Health, National Cancer Institute
Laboratory of Pathology 9000 Rockville Pike
Bethesda, MD 20892
Phone: 301.496.2176
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