Differential expression of genes coding for EGF-like factors and ADAMTS1 following gonadotropin stimulation in normal and transformed human granulosa cells

Sarit Freimann, Ido Ben-Ami, Ada Dantes, Leah Armon, Avital Ben Ya'cov-Klein, Raphael Ron-El, Abraham Amsterdam

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

We have demonstrated previously that the synthesis of epiregulin and amphiregulin, of the EGF-like growth factor family, is stimulated by luteinizing hormone in human follicular (granulosa) cells obtained from in vitro fertilization program. In the present work, we demonstrate that H89, a PKA inhibitor, attenuated the expression of these growth factors both in the mRNA and the protein levels, suggesting PKA involvement in this signaling pathway. SV40-transformed human granulosa cells showed higher basal levels of epiregulin and amphiregulin than normal cells, which were still elevated following cAMP stimulation by Forskolin. Cleavage by a disintegrin and metalloproteinases (ADAMs) is essential for activation of these growth factors, allowing their interaction with EGF receptor. Expression of ADAMTS1 and ADAM12 was downregulated by cAMP in normal, but not in SV40-transformed cells, suggesting that in normal cells epiregulin and amphiregulin activity is downregulated by a feedback mechanism that may be lost in SV40-transformed cells and their loss of downregulation may be involved in the development of ovarian tumors.

Original languageEnglish
Pages (from-to)935-943
Number of pages9
JournalBiochemical and Biophysical Research Communications
Volume333
Issue number3
DOIs
StatePublished - 5 Aug 2005
Externally publishedYes

Funding

We thank Dr. F. Kohen for helpful discussion, and Drs. S. Saban and R. Ophir of the Bioinformatics and Biological computing unit at the Weizmann Institute of Science, for excellent technical assistance in analysis of the DNA array data. This study was supported by Yad-Avraham Center for Cancer Research, by a research grant from Mr. Edgar L. Cadden and La Fundation Raphael et Regina Levy, and by the Women Health Research Center at the Weizmann Institute of Science, Rehovot, Israel. A. Amsterdam is the incumbent of the Joyce and Ben B. Eisenberg Professorial Chair in Molecular Endocrinology and Cancer Research at the Weizmann Institute of Science.

FundersFunder number
La Fundation Raphael et Regina Levy
Weizmann Institute of Science, Rehovot, Israel
Women Health Research Center
Yad-Avraham Center for Cancer Research

    Keywords

    • Amphiregulin
    • Desensitization
    • Epiregulin
    • Metalloproteinase
    • Ovary
    • SV40 oncogene

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