BONE CELL PROTO-ONCOGENE PROMOTERS

  • Spelsberg, Thomas C (PI)

Project: Research project

Project Details

Description

Recent advances have now implicated both osteoblasts and osteoclasts as
target cells for steroid hormones including estrogen (E2) It is the
hypothesis of this laboratory that estrogen (E2) plays a major role in
the coupling of bone resorbing osteoclasts and bone forming osteoblasts
and is involved in osteoporosis. Our laboratories discovered estrogen
receptors (as well as progesterone and androgen receptors) in normal
human osteoblast-like (hOB) cells and steroid receptors in avian
osteoclasts. However, we have identified no E2 effects on cell
proliferation or matrix protein production in normal human osteoblast
cells, but have identified a significant E2 induction of TGF-beta in
these cultured (hOB) cells. TGF-beta appears to play a key role in E2
action on bone. Since the TGF-beta gene was reported to be regulated by
Fos/Jun, we then investigated and have preliminary results which
demonstrate that E2 rapidly and markedly regulates the steady state mRNA
levels of the c-fos and c-jun nuclear proto-oncogenes in the hOB cells.
The goal of this application is to further characterize the rapid E2
regulation of these protooncogenes in the hOB cells by identifying the
transcriptional regulatory elements for E2. We will continue studies on
the regulation of c-fos and c-jun mRNA steady state levels in hOB cells
in response to E2, l7alphaE2 (inactive) or 4-hydroxytamoxifen (anti-E2).
We have succeeded in (and will continue) transfection of the c-fos/CAT
and cjun/CAT constructs into hOB cells to demonstrate the E2 regulation
of the transfected genes. Using deletion mutants of the c-fos and c-jun
5' domains, it is hoped that all sequences required for E2 response will
be identified. Verification of these putative E2 functional elements
will be achieved using oligonucleotides containing these elements in
tk/CAT constructs. We will assess both normal hOB cells, other bone
cells, and reproductive cells for differences in the regulation of these
elements. Final studies will focus on the analyses of nuclear protein
factors from hOB cells, other bone cells, and reproductive cells which
bind specifically to these elements. The characterization of the E2
regulation of these regulatory proto-oncogenes in cells of the osteoblast
lineage should help elucidate the role of E2 in regulating these genes in
normal and pathological states.
StatusFinished
Effective start/end date7/10/925/31/97

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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