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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #148824
Title: SELECTIVE INTERACTIONS OF KLF9/BTEB1 WITH PROGESTERONE RECEPTOR ISOFORMS A AND B DETERMINE TRANSCRIPTIONAL ACTIVITY OF PROGESTERONE-RESPONSIVE GENES IN ENDOMETRIAL EPITHELIAL CELLS

Author
item ZHANG, XUE-LIAN - UNIV. OF FLORIDA
item ZHANG, DAYING - UNIV. OF FLORIDA
item MICHEL, FRANK - UNIV. OF FLORIDA
item BLUM, JASON - UNIV. OF FLORIDA
item SIMMEN, FRANK - UAMS/ACNC
item SIMMEN, ROSALIE - UAMS/ACNC

Submitted to: Journal of Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/15/2003
Publication Date: 4/2/2003
Citation: ZHANG, X., ZHANG, D., MICHEL, F.J., BLUM, J.L., SIMMEN, F.A., SIMMEN, R.C. SELECTIVE INTERACTIONS OF KLF9/BTEB1 WITH PROGESTERONE RECEPTOR ISOFORMS A AND B DETERMINE TRANSCRIPTIONAL ACTIVITY OF PROGESTERONE-RESPONSIVE GENES IN ENDOMETRIAL EPITHELIAL CELLS. JOURNAL OF BIOCHEMISTRY. 2003. v. 278. p. 21474-21482.

Interpretive Summary: Progesterone is a steroid hormone produced primarily by the ovary and is involved in many different biological processes. In particular, it is required for establishment and maintenance of pregnancy, and is implicated in the inhibition of abnormal growth processes that could lead to cancer. Progesterone exerts its biological function by binding to a protein present in cells; this protein is called the progesterone receptor. In this study, we examined the mechanism by which the progesterone receptor interacts with other proteins, in particular another cellular protein called Basic Element Binding Protein (BTEB1) to exert its function to regulate mammary and uterine cell growth. This study has potential important applications for understanding how nutritional factors, by influencing progesterone receptor action, protect against the development of breast and uterine cancer.

Technical Abstract: The Sp/XKLF transcription factor BTEB1 regulates gene transcription by binding to GC-rich sequence motifs present in the promoters of numerous tissue-specific as well as housekeeping genes. Similar to other members of this family, BTEB1 can act as a transactivator or transrepressor depending on cell and promoter context, although the molecular mechanism underlying these distinct activities remains unclear. Here we report that BTEB1 can mediate signaling pathways involving the nuclear receptor for the steroid hormone progesterone in endometrial epithelial cells by its selective interaction with the progesterone receptor (PR) isoforms, PR-A and PR-B. Functional interaction with ligand-activated PR-B resulted in superactivation of PR-B transactivity, facilitated the recruitment of the transcriptional integrator CBP within the PR-dimer, and was dependent on the structure of the ligand bound by PR-B. By contrast, BTEB1 did not influence agonist bound PR-A transactivity, although it augmented PR-A inhibition of PR-B-mediated transactivation as well as potentiated ligand-independent PR-A transcriptional activity in the presence of CBP. We also demonstrate similar positive modulatory actions of BTEB1-related family members KLF13/FKLF2/BTEB3 and Sp1 on PR-B transactivity. Further, we provide support for the potential significance of the selective functional interactions of PR isoforms with BTEB1 in the peri-implantation uterus using mouse and pig models and in the breast cancer cell lines MCF-7 and T47D. Our results suggest a novel mechanism for the divergent physiological consequences of PR-A and PR-B on progesterone-dependent gene transcription in the uterus involving select KLF members.