The Krüppel-like Factors in Female Reproductive System Pathologies

Overview

Journal J Mol Endocrinol

Specialties Endocrinology
Molecular Biology

Date 2015 Feb 7

PMID 25654975

Citations 14

Authors

Rosalia C M Simmen

Melissa E Heard

Angela M Simmen

Maria Theresa M Montales

Meera Marji

Samantha Scanlon

John Mark P Pabona

Affiliations

Soon will be listed here.

Abstract

Female reproductive tract pathologies arise largely from dysregulation of estrogen and progesterone receptor signaling, leading to aberrant cell proliferation, survival, and differentiation. The signaling pathways orchestrated by these nuclear receptors are complex, require the participation of many nuclear proteins serving as key binding partners or targets, and involve a range of paracrine and autocrine regulatory circuits. The members of the Krüppel-like factor (KLF) family of transcription factors are ubiquitously expressed in reproductive tissues and have been increasingly implicated as critical co-regulators and integrators of steroid hormone actions. Herein, we explore the involvement of KLF family members in uterine pathology, describe their currently known molecular mechanisms, and discuss their potential as targets for therapeutic intervention.

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References

Zhang Y, Lei C, Hu Y, Xia T, Li M, Zhong B . Krüppel-like factor 6 is a co-activator of NF-κB that mediates p65-dependent transcription of selected downstream genes. J Biol Chem. 2014; 289(18):12876-85. PMC: 4007475. DOI: 10.1074/jbc.M113.535831. View

Sakr S, Naqvi H, Komm B, Taylor H . Endometriosis impairs bone marrow-derived stem cell recruitment to the uterus whereas bazedoxifene treatment leads to endometriosis regression and improved uterine stem cell engraftment. Endocrinology. 2014; 155(4):1489-97. PMC: 3959601. DOI: 10.1210/en.2013-1977. View

Oktem G, Bilir A, Uslu R, Inan S, Demiray S, Atmaca H . Expression profiling of stem cell signaling alters with spheroid formation in CD133/CD44 prostate cancer stem cells. Oncol Lett. 2014; 7(6):2103-2109. PMC: 4049671. DOI: 10.3892/ol.2014.1992. View

Zhang Q, Dou H, Tang Y, Su S, Liu P . Lentivirus-mediated knockdown of Krüppel-like factor 9 inhibits the growth of ovarian cancer. Arch Gynecol Obstet. 2014; 291(2):377-82. DOI: 10.1007/s00404-014-3405-3. View

Zhang X, Zhang D, Michel F, Blum J, Simmen F, Simmen R . Selective interactions of Kruppel-like factor 9/basic transcription element-binding protein with progesterone receptor isoforms A and B determine transcriptional activity of progesterone-responsive genes in endometrial epithelial cells. J Biol Chem. 2003; 278(24):21474-82. DOI: 10.1074/jbc.M212098200. View

Camacho-Vanegas O, Till J, Miranda-Lorenzo I, Ozturk B, Camacho S, Martignetti J . Shaking the family tree: identification of novel and biologically active alternatively spliced isoforms across the KLF family of transcription factors. FASEB J. 2012; 27(2):432-6. DOI: 10.1096/fj.12-220319. View

Funnell A, Mak K, Twine N, Pelka G, Norton L, Radziewic T . Generation of mice deficient in both KLF3/BKLF and KLF8 reveals a genetic interaction and a role for these factors in embryonic globin gene silencing. Mol Cell Biol. 2013; 33(15):2976-87. PMC: 3719677. DOI: 10.1128/MCB.00074-13. View

Ray S, Pollard J . KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing. Proc Natl Acad Sci U S A. 2012; 109(21):E1334-43. PMC: 3361390. DOI: 10.1073/pnas.1118515109. View

Ying M, Tilghman J, Wei Y, Guerrero-Cazares H, Quinones-Hinojosa A, Ji H . Kruppel-like factor-9 (KLF9) inhibits glioblastoma stemness through global transcription repression and integrin α6 inhibition. J Biol Chem. 2014; 289(47):32742-56. PMC: 4239625. DOI: 10.1074/jbc.M114.588988. View

10.

Yusuf I, Kharas M, Chen J, Peralta R, Maruniak A, Sareen P . KLF4 is a FOXO target gene that suppresses B cell proliferation. Int Immunol. 2008; 20(5):671-81. DOI: 10.1093/intimm/dxn024. View

11.

Shimizu Y, Takeuchi T, Mita S, Notsu T, Mizuguchi K, Kyo S . Krüppel-like factor 4 mediates anti-proliferative effects of progesterone with G₀/G₁ arrest in human endometrial epithelial cells. J Endocrinol Invest. 2010; 33(10):745-50. DOI: 10.1007/BF03346681. View

12.

Dasgupta S, OMalley B . Transcriptional coregulators: emerging roles of SRC family of coactivators in disease pathology. J Mol Endocrinol. 2014; 53(2):R47-59. PMC: 4152414. DOI: 10.1530/JME-14-0080. View

13.

Alder J, Georgantas 3rd R, Hildreth R, Kaplan I, Morisot S, Yu X . Kruppel-like factor 4 is essential for inflammatory monocyte differentiation in vivo. J Immunol. 2008; 180(8):5645-52. PMC: 3074963. DOI: 10.4049/jimmunol.180.8.5645. View

14.

Chan R, Ng E, Yeung W . Identification of cells with colony-forming activity, self-renewal capacity, and multipotency in ovarian endometriosis. Am J Pathol. 2011; 178(6):2832-44. PMC: 3123988. DOI: 10.1016/j.ajpath.2011.02.025. View

15.

Adammek M, Greve B, Kassens N, Schneider C, Bruggemann K, Schuring A . MicroRNA miR-145 inhibits proliferation, invasiveness, and stem cell phenotype of an in vitro endometriosis model by targeting multiple cytoskeletal elements and pluripotency factors. Fertil Steril. 2013; 99(5):1346-1355.e5. DOI: 10.1016/j.fertnstert.2012.11.055. View

16.

de Assuncao T, Lomberk G, Cao S, Yaqoob U, Mathison A, Simonetto D . New role for Kruppel-like factor 14 as a transcriptional activator involved in the generation of signaling lipids. J Biol Chem. 2014; 289(22):15798-809. PMC: 4140934. DOI: 10.1074/jbc.M113.544346. View

17.

Nelson S, Telfer E, Anderson R . The ageing ovary and uterus: new biological insights. Hum Reprod Update. 2012; 19(1):67-83. PMC: 3508627. DOI: 10.1093/humupd/dms043. View

18.

Simmons C, Pabona J, Heard M, Friedman T, Spataro M, Godley A . Krüppel-like factor 9 loss-of-expression in human endometrial carcinoma links altered expression of growth-regulatory genes with aberrant proliferative response to estrogen. Biol Reprod. 2011; 85(2):378-85. PMC: 3142261. DOI: 10.1095/biolreprod.110.090654. View

19.

Rackow B, Taylor H . Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil Steril. 2008; 93(6):2027-34. PMC: 3107853. DOI: 10.1016/j.fertnstert.2008.03.029. View

20.

Natesampillai S, Kerkvliet J, Leung P, Veldhuis J . Regulation of Kruppel-like factor 4, 9, and 13 genes and the steroidogenic genes LDLR, StAR, and CYP11A in ovarian granulosa cells. Am J Physiol Endocrinol Metab. 2007; 294(2):E385-91. PMC: 2747322. DOI: 10.1152/ajpendo.00480.2007. View