عنوان

The role of nuclear IGF-I receptor in diethylstilbestrol (DES)-induced cell proliferation

Number

TLpq304235020

.Language of Text, Soundtrack etc

انگلیسی

Title Proper

The role of nuclear IGF-I receptor in diethylstilbestrol (DES)-induced cell proliferation

General Material Designation

[Thesis]

First Statement of Responsibility

C.-W. Chen

Subsequent Statement of Responsibility

D. Roy

Name of Publisher, Distributor, etc.

The University of Alabama at Birmingham

Date of Publication, Distribution, etc.

1996

Specific Material Designation and Extent of Item

138

Dissertation or thesis details and type of degree

Ph.D.

Body granting the degree

The University of Alabama at Birmingham

Text preceding or following the note

1996

Text of Note

Estrogens are carcinogenic to both rodents and humans. In animals, stilbene estrogen, diethylstilbestrol (DES) acts as both initiator and promotor. The mechanism by which DES influences proliferation of normal and transformed cells is not clear. The objective of the present research was to investigate the role of nuclear insulin-like growth factor-I receptor (nIGF-IR) in estrogen-induced cell proliferation. It is proposed that acute exposure to animals with DES leads to overexpression of nlGF-IRs, which provides stimuli for uncontrolled cell proliferation in the target organ of carcinogenesis (Syrian hamster kidney). For the first time, the presence of IGF-IR on the nucleus of hamster renal epithelial cells was detected by binding assay, affinity labeling and Western blotting assays. And the nuclear localization of IGF-IRs was confirmed by immunofluorescence staining. The DES-stimulated nIGF-IR in nuclei was demonstrated by receptor binding, affinity labeling and Western blotting assays. It was observed that DES exerted both dose- and time-dependent increases on renal epithelial cell proliferation. In addition, the DES treatment also enhanced IGF-IR gene expression. Pretreatment of an antiestrogenic compound, ICI182780, strongly attenuated the DES-stimulated cell proliferation, and also inhibited the DES-induced IGF-IR gene expression. Moreover, cotreatment of cells with an anti-IGF-IR antibody (usd\alphausdIR3) significantly attenuated the growth-stimulatory effects of DES. The receptor binding assay revealed that nuclear usd\rm \lbrack \sp{125}I\rbrackusdIGF-I specific binding was doubled by DES treatment. Cotreatment of cells with a plant flavone, luteolin, and DES resulted in a 78% reduction in cell growth compared to DES alone. DES-induced IGF-I receptor gene expression was effectively attenuated by the presence of luteolin. Moreover, the nuclear tyrosine kinase activity was also inhibited in a dose-dependent manner by luteolin. These findings suggested that the up-regulation of nIGF-IR coupled with enhanced cell proliferation by short term exposure of DES may play an important role in the induction of estrogen-induced carcinogenesis.

Cell proliferation

Diethylstilbestrol

Health and environmental sciences

insulin like growth factor I

Nuclear IGF-I receptor

Toxicology

C.-W. Chen

D. Roy

Electronic name

p

[Thesis]

276903

a

Y