Regulation of Insulin-Like Growth Factor Binding Protein-1 Promoter Activity by FKHR and HOXA10 in Primate Endometrial Cells1

Abstract

Insulin-like growth factor binding protein-1 (IGFBP-1) is abundantly expressed in the liver and decidualized endometrium. FKHR, a FOXO forkhead transcription factor, stimulates IGFBP-1 promoter activity in liver cells through the insulin response sequences (IRSs). HOXA10, a homeobox transcription factor, is important in the decidualization process. Here we show that FKHR and HOXA10 are expressed in baboon endometrium during the menstrual cycle and pregnancy. Levels are lowest during the follicular phase and highest in pregnancy. Reporter gene studies reveal that FKHR stimulates both baboon and human IGFBP-1 promoter activity, whereas HOXA10 alone has a relatively weak effect. When FKHR and HOXA10 are expressed together, promoter activity is markedly up-regulated, which is indicative of cooperativity. A DNA binding-deficient FKHR mutant fails to stimulate promoter activity, even in the presence of HOXA10, and deletion or mutation of IRSs also disrupts the effect of FKHR and cooperativity with HOXA10. Conversely, the IRS region placed upstream of the 31 base pair IGFBP-1 minimal promoter is sufficient to mediate effects of FKHR and cooperativity with HOXA10. Pull-down studies reveal physical association between GST-FKHR and (35)S-HOXA10. These studies show that FKHR and HOXA10 interact directly and can function cooperatively to stimulate IGFBP-1 promoter activity in endometrial cells and perhaps in other settings.

FOXO-binding partners: it takes two to tango

“…The cooperative action of FOXO transcription factors in endometrial decidualization is not only restricted to C/EBPb. The homeobox (HOX) protein HOXA10 also follows similar patterns of expression to FOXO1 during different stages of the baboon menstrual cycle and pregnancy (Kim et al, 2003). HOX proteins are developmentally regulated transcription factors that are important for spatial identity and differentiation of tissues in the developing embryo.…”

“…HOXA10 null mutant mice exhibit infertility due to compromised endometrial decidualization during blastocyst implantation (Benson et al, 1996). Kim et al were able to demonstrate a direct in vitro association between HOXA10 and FOXO1 as well as cooperative transactivation of the insulin-like growth factor-binding protein-1 (IGFBP-1) promoter (Kim et al, 2003). During pregnancy IGFBP-1 is expressed in decidualized stromal cells where it is thought to play a role during blastocyst implantation (Giudice et al, 1993).…”

The distal upstream region of insulin-like growth factor–binding protein-1 enhances its expression in endometrial stromal cells during decidualization

“…Only the roles of the proximal promoter region and transcription factors in the regulation of IGFBP-1 expression have been reported so far (13)(14)(15)(16).…”

B-cell development in the presence of the MLL/AF4 oncoprotein proceeds in the absence of HOX A7 and HOX A9 expression

“…However, lack of HOX A7 and HOX A9 expression blocks Hox/Meis/Pbx-mediated enhancement of MLL oncogenesis, resulting in the retention of normal B-developmental features. Interestingly, HOX A5 and HOX A10 have been shown to interact with FKHR regulating IGFBP-1 expression, 42,43 providing a potential pathway leading from altered HOX gene expression to loss of stromal cell/growth factor dependency in MLL leukemia. As recent studies have indicated that mechanisms of HOX gene regulation differ between wild-type MLL and truncated MLL, 16 BLIN-3 is a useful model for examining the regulation and potential requirement for HOX gene expression in MLL-mediated oncogenesis during human B-cell development.…”