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1.
Life Sci Alliance ; 2(3)2019 06.
Article in English | MEDLINE | ID: mdl-31167803

ABSTRACT

WT1 is a transcriptional activator that controls the boundary between multipotency and differentiation. The transcriptional cofactor BASP1 binds to WT1, forming a transcriptional repressor complex that drives differentiation in cultured cells; however, this proposed mechanism has not been demonstrated in vivo. We used the peripheral taste system as a model to determine how BASP1 regulates the function of WT1. During development, WT1 is highly expressed in the developing taste cells while BASP1 is absent. By the end of development, BASP1 and WT1 are co-expressed in taste cells, where they both occupy the promoter of WT1 target genes. Using a conditional BASP1 mouse, we demonstrate that BASP1 is critical to maintain the differentiated state of adult taste cells and that loss of BASP1 expression significantly alters the composition and function of these cells. This includes the de-repression of WT1-dependent target genes from the Wnt and Shh pathways that are normally only transcriptionally activated by WT1 in the undifferentiated taste cells. Our results uncover a central role for the WT1-BASP1 complex in maintaining cell differentiation in vivo.


Subject(s)
Calmodulin-Binding Proteins/metabolism , Cell Differentiation , Cytoskeletal Proteins/metabolism , Nerve Tissue Proteins/metabolism , Taste Buds/cytology , Taste Buds/metabolism , WT1 Proteins/metabolism , Animals , Biomarkers , Calmodulin-Binding Proteins/genetics , Cell Differentiation/genetics , Cytoskeletal Proteins/genetics , Fluorescent Antibody Technique , Gene Expression , Gene Knockdown Techniques , Mice , Mice, Transgenic , Models, Biological , Nerve Tissue Proteins/genetics , Phenotype , Protein Binding , WT1 Proteins/genetics
2.
Cell Death Dis ; 8(5): e2771, 2017 05 11.
Article in English | MEDLINE | ID: mdl-28492543

ABSTRACT

Tamoxifen binds to oestrogen receptor α (ERα) to elicit distinct responses that vary by cell/tissue type and status, but the factors that determine these differential effects are unknown. Here we report that the transcriptional corepressor BASP1 interacts with ERα and in breast cancer cells, this interaction is enhanced by tamoxifen. We find that BASP1 acts as a major selectivity factor in the transcriptional response of breast cancer cells to tamoxifen. In all, 40% of the genes that are regulated by tamoxifen in breast cancer cells are BASP1 dependent, including several genes that are associated with tamoxifen resistance. BASP1 elicits tumour-suppressor activity in breast cancer cells and enhances the antitumourigenic effects of tamoxifen treatment. Moreover, BASP1 is expressed in breast cancer tissue and is associated with increased patient survival. Our data have identified BASP1 as an ERα cofactor that has a central role in the transcriptional and antitumourigenic effects of tamoxifen.


Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Estrogen Receptor alpha/biosynthesis , Gene Expression Regulation, Neoplastic/drug effects , Membrane Proteins/biosynthesis , Neoplasm Proteins/biosynthesis , Nerve Tissue Proteins/biosynthesis , Repressor Proteins/biosynthesis , Tamoxifen/pharmacology , Transcription, Genetic/drug effects , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Estrogen Receptor alpha/genetics , Female , Humans , K562 Cells , MCF-7 Cells , Membrane Proteins/genetics , Neoplasm Proteins/genetics , Nerve Tissue Proteins/genetics , Repressor Proteins/genetics
3.
Transcription ; 1(3): 126-129, 2010 Nov.
Article in English | MEDLINE | ID: mdl-21326885

ABSTRACT

The general transcription factor TFIIB plays essential, but as yet unclear, roles in transcription initiation by RNA polymerase II. We recently found that phosphorylation of TFIIB is required for productive transcription. We discuss the implications of this work for the functions of TFIIB in promoter escape and gene loop formation.

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