title: Involvement of KLF14 and egr-1 in the TGF-beta1 action on Leydig cell proliferation.
abstract: Transforming growth factor β1 (TGF-β1) is a pleiotropic cytokine that modulates cell homeostasis. In Leydig cells, TGF-β1 exerts stimulatory and inhibitory effect depending on the type I receptor involved in the signaling pathway. The aim of the present work was to study the signaling mechanisms and the intermediates involved in the action of TGF-β1 on TM3 Leydig cell proliferation in the presence or absence of progesterone. The MTT assay showed that the presence of progesterone in the culture media lead to a proliferative effect that was blocked by Ru 486, an inhibitor of progesterone receptor; and ALK-5 did not participate in this effect. TGF-β1 (1 ng/ml) increased the expression of p15 (an inhibitor of cell cycle) in TM3 Leydig cells, and this effect was blocked by progesterone (1μM). The expression of PCNA presented a higher increase in the cell cultured with TGF-β1 plus progesterone than in cells cultured only with TGF-β1. Progesterone induced the gene expression of endoglin, a cofactor of TGF-β1 receptor that leads to a stimulatory signaling pathway, despite of the absence of progesterone response element in endoglin gene. In addition, the presence of progesterone induced the gene expression of egr-1 and also KLF14, indicating that this steroid channels the signaling pathway into a non-canonical mechanism. In conclusion, these findings suggest that the proliferative action of TGF-β1 involves endoglin. This co-receptor might be induced by KLF14 which is probably activated by progesterone.
authors: Research Center of Biomedical Biotechnology, Environmental and Diagnostic Studies, Maimónides University, Hidalgo 775, 1405 Buenos Aires, Argentina. gonzalez.candela@maimonides.edu
authors: C R
authors: CR
authors: Gonzalez
authors: S S
authors: SS
authors: Vallcaneras
authors: R S
authors: RS
authors: Calandra
authors: S I
authors: SI
authors: Gonzalez Calvar
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D030301:Activin Receptors, Type II; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D000071063:Endoglin; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D007985:Leydig Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011374:Progesterone / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D018076:DNA, Complementary; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C558181:Klf14 protein, mouse; D051741:Kruppel-Like Transcription Factors; D018809:Proliferating Cell Nuclear Antigen; D018125:Receptors, Transforming Growth Factor beta; C508961:Tgfb1 protein, mouse; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D011374:Progesterone; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse