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

Publication ,  Journal Article
Yoo, J-Y; Kim, TH; Fazleabas, AT; Palomino, WA; Ahn, SH; Tayade, C; Schammel, DP; Young, SL; Jeong, J-W; Lessey, BA
Published in: Sci Rep
July 28, 2017

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.

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Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

July 28, 2017

Volume

7

Issue

1

Start / End Page

6765

Location

England

Related Subject Headings

  • Zinc Finger Protein GLI1
  • Young Adult
  • Uterus
  • Uterine Diseases
  • Transcription, Genetic
  • Sirtuin 1
  • Proto-Oncogene Proteins p21(ras)
  • Proto-Oncogene Proteins c-bcl-6
  • Papio
  • Middle Aged
 

Citation

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ICMJE
MLA
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Yoo, J.-Y., Kim, T. H., Fazleabas, A. T., Palomino, W. A., Ahn, S. H., Tayade, C., … Lessey, B. A. (2017). KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance. Sci Rep, 7(1), 6765. https://doi.org/10.1038/s41598-017-04577-w
Yoo, Jung-Yoon, Tae Hoon Kim, Asgerally T. Fazleabas, Wilder A. Palomino, Soo Hyun Ahn, Chandrakant Tayade, David P. Schammel, Steven L. Young, Jae-Wook Jeong, and Bruce A. Lessey. “KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance.Sci Rep 7, no. 1 (July 28, 2017): 6765. https://doi.org/10.1038/s41598-017-04577-w.
Yoo J-Y, Kim TH, Fazleabas AT, Palomino WA, Ahn SH, Tayade C, et al. KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance. Sci Rep. 2017 Jul 28;7(1):6765.
Yoo, Jung-Yoon, et al. “KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance.Sci Rep, vol. 7, no. 1, July 2017, p. 6765. Pubmed, doi:10.1038/s41598-017-04577-w.
Yoo J-Y, Kim TH, Fazleabas AT, Palomino WA, Ahn SH, Tayade C, Schammel DP, Young SL, Jeong J-W, Lessey BA. KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance. Sci Rep. 2017 Jul 28;7(1):6765.

Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

July 28, 2017

Volume

7

Issue

1

Start / End Page

6765

Location

England

Related Subject Headings

  • Zinc Finger Protein GLI1
  • Young Adult
  • Uterus
  • Uterine Diseases
  • Transcription, Genetic
  • Sirtuin 1
  • Proto-Oncogene Proteins p21(ras)
  • Proto-Oncogene Proteins c-bcl-6
  • Papio
  • Middle Aged