HORMONAL CONTROL OF PROLIFERATION OF MALIGNANT THYMOCYTE

Project: Research project

Description

Clonal subpopulations have been isolated from lymphosarcoma P1798, and
glucocorticoid-resistant variants were selected in culture and in vivo.
Variants that are resistant to the cytolytic effects of glucocorticoids in
vivo express near wild-type levels of glucocorticoid binding and normal
levels of nuclear translocation of the hormone-receptor complex. Injection
of dexamethasone (dex) into tumor-bearing mice results in essentially
complete saturation of the receptor within 2 hrs, and wild-type and
resistant tumor cells are identical with respect to the kinetics and extent
of hormone binding in vivo. The modal number of chromosomes does not
change during selection in vivo. P1798 cells were infected with mouse
mammary tumor virus (MMTV), and induction of MMTV RNA synthesis was
measured as an indicator of glucocorticoid receptor function. Treatment
with dex in culture and in vivo stimulated MMTV expression in wild-type
cells and in resistant variants. Moreover, variants that were selected for
resistance in vivo were completely sensitive to the receptor-mediated
antiproliferative effects of dex in culture. These data clearly indicate
that selection for glucocorticoid resistance in vivo does not result in
loss of receptor function. Glucocorticoid-resistant variants selected in
culture expressed classical receptor-defective phenotypes including reduced
total hormone binding and nuclear translocation of the hormone-receptor
complex. Such variants grew at wild-type rates in the presence of dex in
culture, but all such isolates were sensitive to the cytolytic effects of
glucocorticoids in vivo. In summary, variants selected in vivo expressed
functional glucocorticoid receptors and were sensitive to glucocorticoids
in culture. Conversely, variants selected in culture expressed defective
receptors and were sensitive to the cytolytic effects of the hormone in
vivo. We conclude that the pharmacological effects of glucocorticoids in
vivo are independent of, or superimposed upon, the physiological (i.e.,
receptor-mediated) effects of the hormone. Our working hypothesis is that
glucocorticoid receptors may have little or nothing to do with cytolysis in
vivo. (D)
StatusFinished
Effective start/end date4/1/796/30/06

Funding

  • National Institutes of Health
  • National Institutes of Health: $380,391.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $369,309.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $348,110.00
  • National Institutes of Health
  • National Institutes of Health: $358,554.00
  • National Institutes of Health
  • National Institutes of Health: $337,969.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $168,342.00
  • National Institutes of Health

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Glucocorticoids
Thymocytes
Cyclin D3
Dexamethasone
Hormones
Lymphocytes
Steroids
Oncogenic Viruses
Glucocorticoid Receptors
Cell Death
Messenger RNA
Genes
Phenotype
Cell Cycle
3' Untranslated Regions
Virus Activation
DNA
Pharmacology
Cell Proliferation
Drug Therapy

ASJC

  • Medicine(all)