KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance

Abstract Endometriosis is an inflammatory condition that is associated with progesterone resistance and cell proliferation, resulting in pain, infertility and pregnancy loss. We previously demonstrated phosphorylation of STAT3 in eutopic endometrium of infertile women with this disorder leading to o...

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Autores principales:	Jung-Yoon Yoo, Tae Hoon Kim, Asgerally T. Fazleabas, Wilder A. Palomino, Soo Hyun Ahn, Chandrakant Tayade, David P. Schammel, Steven L. Young, Jae-Wook Jeong, Bruce A. Lessey
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8511e65b6d0145d4b9e1880673eb0c3f
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spelling	oai:doaj.org-article:8511e65b6d0145d4b9e1880673eb0c3f2021-12-02T11:53:02ZKRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance10.1038/s41598-017-04577-w2045-2322https://doaj.org/article/8511e65b6d0145d4b9e1880673eb0c3f2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04577-whttps://doaj.org/toc/2045-2322Abstract Endometriosis is an inflammatory condition that is associated with progesterone resistance and cell proliferation, resulting in pain, infertility and pregnancy loss. We previously demonstrated phosphorylation of STAT3 in eutopic endometrium of infertile women with this disorder leading to over-expression of the oncogene BCL6 and stabilization of hypoxia-induced factor 1 alpha (HIF-1α). Here we report coordinated activation of KRAS and over-expression of Sirtuin 1 (SIRT1), a histone deacetylase and gene silencer, in the eutopic endometrium from women with endometriosis throughout the menstrual cycle. The mice with conditional activation of KRAS in the PGR positive cells reveal an increase of SIRT1 expression in the endometrium compared to control mice. The expression of progesterone receptor target genes including the Indian Hedgehog pathway genes are significantly down-regulated in the mutant mice. SIRT1 co-localizes with BCL6 in the nuclei of affected individuals and both proteins bind to and suppress the promoter of GLI1, a critical mediator of progesterone action in the Indian Hedgehog pathway, by ChIP analysis. In eutopic endometrium, GLI1 expression is reduced in women with endometriosis. Together, these data suggest that KRAS, SIRT1 and BCL6 are coordinately over-expressed in eutopic endometrium of women with endometriosis and likely participate in the pathogenesis of endometriosis.Jung-Yoon YooTae Hoon KimAsgerally T. FazleabasWilder A. PalominoSoo Hyun AhnChandrakant TayadeDavid P. SchammelSteven L. YoungJae-Wook JeongBruce A. LesseyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jung-Yoon Yoo Tae Hoon Kim Asgerally T. Fazleabas Wilder A. Palomino Soo Hyun Ahn Chandrakant Tayade David P. Schammel Steven L. Young Jae-Wook Jeong Bruce A. Lessey KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance
description	Abstract Endometriosis is an inflammatory condition that is associated with progesterone resistance and cell proliferation, resulting in pain, infertility and pregnancy loss. We previously demonstrated phosphorylation of STAT3 in eutopic endometrium of infertile women with this disorder leading to over-expression of the oncogene BCL6 and stabilization of hypoxia-induced factor 1 alpha (HIF-1α). Here we report coordinated activation of KRAS and over-expression of Sirtuin 1 (SIRT1), a histone deacetylase and gene silencer, in the eutopic endometrium from women with endometriosis throughout the menstrual cycle. The mice with conditional activation of KRAS in the PGR positive cells reveal an increase of SIRT1 expression in the endometrium compared to control mice. The expression of progesterone receptor target genes including the Indian Hedgehog pathway genes are significantly down-regulated in the mutant mice. SIRT1 co-localizes with BCL6 in the nuclei of affected individuals and both proteins bind to and suppress the promoter of GLI1, a critical mediator of progesterone action in the Indian Hedgehog pathway, by ChIP analysis. In eutopic endometrium, GLI1 expression is reduced in women with endometriosis. Together, these data suggest that KRAS, SIRT1 and BCL6 are coordinately over-expressed in eutopic endometrium of women with endometriosis and likely participate in the pathogenesis of endometriosis.
format	article
author	Jung-Yoon Yoo Tae Hoon Kim Asgerally T. Fazleabas Wilder A. Palomino Soo Hyun Ahn Chandrakant Tayade David P. Schammel Steven L. Young Jae-Wook Jeong Bruce A. Lessey
author_facet	Jung-Yoon Yoo Tae Hoon Kim Asgerally T. Fazleabas Wilder A. Palomino Soo Hyun Ahn Chandrakant Tayade David P. Schammel Steven L. Young Jae-Wook Jeong Bruce A. Lessey
author_sort	Jung-Yoon Yoo
title	KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance
title_short	KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance
title_full	KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance
title_fullStr	KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance
title_full_unstemmed	KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance
title_sort	kras activation and over-expression of sirt1/bcl6 contributes to the pathogenesis of endometriosis and progesterone resistance
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8511e65b6d0145d4b9e1880673eb0c3f
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KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance

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