Accession Number:

ADA478665

Title:

Forkhead Box Protein 1 (Foxa1) and the Sumoylation Pathway that Regulates Foxa1 Stability are Potential Targets for Breast Cancer Treatment

Descriptive Note:

Final rept. 7 Aug 2006-6 Aug 2007

Corporate Author:

BAYLOR COLL OF MEDICINE HOUSTON TX

Personal Author(s):

Report Date:

2007-09-01

Pagination or Media Count:

9.0

Abstract:

The purpose of this study is to determine the mechanisms by which the posttranslational SUMO modification regulates the activity of the forkhead box protein A1 Foxa 1. Major findings We have demonstrated the sumoylation of Foxa 1 in several breast cancer cell lines. Analysis of the Foxa 1 protein sequence identified two potential sumoylation sites. Lysine to arginine substitution of the conserved lysine K6 abolished Foxa 1 sumoylation suggesting that the K6 is the primary sumoylation site. In contrast to the related forkhead box protein A2 Foxa 2 in which the K6R mutation induced protein destabilization, mutation of the conserved K6 sumoylation site did not strongly affect the stability of the Foxa1 protein. In transfection experiments, Foxa1 induced activation of the p27Kip 1 promoter activity was downregulated by SUMO-1 demonstrating that SUMO-1 negatively regulates Foxa 1 activity. On the contrary, the nonsumoylatable mutant of Foxa 1 Foxa 1 K6R activated the p27Kip 1 promoter to a lower extent compared with the wild type Foxa 1 suggesting that the K6 and its modifications are required for the transcriptional activity of Foxa 1. Together, our results show that Foxa 1 is modified by sumoylation on lysine, K6, and the SUMO modification of Foxa1 modulates the activity of Foxa 1 on its target genes in breast cancer cells.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE