Abstract
The Sp/KLF transcription factor basic transcription element-binding protein (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 CREB-binding protein 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 CREB-binding protein. We also demonstrate similar positive modulatory actions of BTEB1-related family members Krüppel-like family (KLF) 13/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.
Highlights
Progesterone (P)1 plays a predominant role in the control of uterine endometrial growth and differentiation [1]
These results suggest that the selective utilization of BTEB1 and related Kruppel-like family (KLF) members by progesterone receptor (PR) isoforms may underlie, in part, the distinct repertoire of progestin-regulated genes mediated by homodimers of PR-A and PR-B as well as by the PR-A/PR-B heterodimer, respectively, in target cells [29]
Lack of Functional Interaction of the PR-A Isoform with BTEB1—To investigate whether the PR-A isoform interacts with BTEB1, as was previously demonstrated for PR-B [24], two functional assays involving the quantification of promoterreporter activities in cells transiently transfected with expression constructs for PR-A and BTEB1 were utilized
Summary
P, progesterone; KLF, Kruppel-like factor; PR, progesterone receptor; BTEB, basic transcription elementbinding protein; DMEM, Dulbecco’s minimal essential medium; ECL, enhanced chemiluminescence; UF, uteroferrin; Luc, luciferase; CAT, sence of P, the unopposed actions of estrogen can lead to uncontrolled cellular proliferation at the expense of cellular differentiation, an event highly correlated with the development of endometrial carcinoma [2,3]. Promoter as well as cellular context can influence the transcriptional activity of each chloramphenicol acetyltransferase; MMTV, mouse mammary tumor virus; CREB, cAMP-response element-binding protein; CBP, CREBbinding protein; FBS, fetal bovine serum; TFBS, Tet system approved fetal bovine serum; LSM, least-square means; ANOVA, analysis of variance; SRC-1, steroid receptor co-activator-1; Dox, doxycycline. We provide evidence to suggest that the functional interactions of BTEB1 and PR-B noted from transient transfection studies may be biologically relevant in the context of early pregnancy in the mouse and pig uterus and in the breast carcinoma cell lines MCF-7 and T47D These results suggest that the selective utilization of BTEB1 and related KLF members by PR isoforms may underlie, in part, the distinct repertoire of progestin-regulated genes mediated by homodimers of PR-A and PR-B as well as by the PR-A/PR-B heterodimer, respectively, in target cells [29]
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