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Title: FUNCTIONAL ROLE OF THE KRUPPEL-LIKE TRANSCRIPTION FACTOR BTEB1 DURING PREGNANCY: STUDIES WITH THE BTEB1 KNOCK-OUT MOUSE

Author
item SIMMEN, ROSALIA - UAMS
item MCQUOWN, JANNELLE - UNIV OF FLORIDA
item KANG, TAEJUNG - UNIV OF FLORIDA
item FUJII-KURIYAMA, YOSHIAKI - UNIV OF FLORIDA
item SIMMEN, FRANK - UAMS
item OH, PAUL - UNIV OF FLORIDA

Submitted to: Society for the Study of Reproduction Annual Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 5/15/2003
Publication Date: 7/19/2003
Citation: SIMMEN, R.C., MCQUOWN, J.R., KANG, T., FUJII-KURIYAMA, Y., SIMMEN, F.A., OH, P.S. FUNCTIONAL ROLE OF THE KRUPPEL-LIKE TRANSCRIPTION FACTOR BTEB1 DURING PREGNANCY: STUDIES WITH THE BTEB1 KNOCK-OUT MOUSE. SOCIETY FOR THE STUDY OF REPRODUCTION ANNUAL MEETING. 2003. v. 68. p. 356. Abstract No. 592.

Interpretive Summary: Breast and prostate cancers are hormone sensitive cancers. The ACNC is interested in the dietary prevention of these cancers and especially in the effects of early diet such as soy infant formula. The steroid hormone progesterone is essential for the proper functioning of several organs, including the mammalian mammary gland and uterus due to its varied effects on proliferation, differentiation, and apoptosis. These various functions of progesterone, which occur by its interaction with a nuclear protein progesterone receptor, are also influenced by other nuclear proteins that interact with the progesterone receptor in target tissues. We have recently identified a novel progesterone receptor interacting protein termed Basic Transcription Element Binding Protein-1 (BTEB1). In this study we used female mice whose gene for BTEB1 was essentially removed by genetic engineering techniques. We show that these mice exhibit reproductive problems which include smaller number of pups born per mother, greater frequency of death in these new born pups, and smaller uteri. These results suggest that interaction of BTEB1 with progesterone receptor is important in achieving successful pregnancy. This gene will be further studied to determine its involvement in hormone sensitive cancers and dietary prevention of these cancers.

Technical Abstract: We have previously identified the Kruppel-like factor (KLF) family member, Basic Transcription Element Binding Protein 1 (BTEB1) as a progesterone receptor (PR) interacting co-regulatory factor that enhances progestin-induced PR transactivation of target genes in uterine endometrial cells in vitro. To begin to elucidate the biological relevance of BTEB1/PR interactions in pregnancy, we determined the pattern of uterine BTEB1 expression in pregnant mice, and utilized female mice null for BTEB1 to evaluate the consequence of BTEB1 gene ablation on reproduction. Western blot analysis indicated robust expression of uterine BTEB1, with no drastic changes observed across pregnancy. BTEB1 null mice were generated by insertion of the LacZ gene into the open reading frame of the first exon of the BTEB1 gene. Homozygous and heterozygous female and male mice were viable, fertile, and matured normally. Female mice of all 3 genotypes had normal estrous cycle duration. However, mice null for BTEB1 (-/-) had reduced litter size relative to wild-type (WT) or heterozygous (+/-) counterparts. In particular, (-/-) mice had an average of 4.7 pups (n=24 litters) compared to 6.7 (n=29 litters) and 7.3 (n=10 litters) for (+/-) and WT, respectively. Pups born from these mothers had comparable birth weights. Using X-gal staining in (+/-) mice, uterine BTEB1 expression was localized to endometrial stromal and glandular but not luminal epithelial, cells as well as to the myometrium as early as gestation day 0.5, and was lacking in the decidua. Further analysis of this mouse model for its reproductive phenotype will provide important insights into PR-related signaling in the uterus that may be essential for successful pregnancy. Supported in part by NIH HD 21961 (RCMS and FAS) and by USDA-CRIS6251-5100-002-06S.