Am J Cancer Res 2012;2(5):549-565
Original Article
RanBPM expression regulates transcriptional pathways involved in
development and tumorigenesis
Elnaz Atabakhsh, Jean H Wang, Xu Wang, David E Carter, Caroline Schild-Poulter
Robarts Research Institute and Department of Biochemistry, Schulich School of Medicine & Dentistry, Western University,
London, Ontario, N6A 5K8, Canada
Received July 5, 2012; accepted August 9, 2012; Epub August 20, 2012; Published September 15, 2012
Abstract: RanBPM is a ubiquitous protein that has been reported to regulate several cellular processes through interactions
with various proteins. However, it not known whether RanBPM may regulate gene expression patterns. As it has been shown that
RanBPM interacts with a number of transcription factors, we hypothesized that it may have wide ranging effects on gene
expression that may explain its function. To test this hypothesis, we generated stable RanBPM shRNA cell lines to analyze the
effect of RanBPM on global gene expression. Microarray analyses were conducted comparing the gene expression profile of
Hela and HCT116 RanBPM shRNA cells versus control shRNA cells. We identified 167 annotated genes significantly up- or
down-regulated in the two cell lines. Analysis of the gene set revealed that down-regulation of RanBPM led to gene expression
changes that affect regulation of cell, tissue, and organ development and morphology, as well as biological processes
implicated in tumorigenesis. Analysis of Transcription Factor Binding Sites (TFBS) present in the gene set identified several
significantly over-represented transcription factors of the Forkhead, HMG, and Homeodomain families of transcription factors,
which have previously been demonstrated as having important roles in development and tumorigenesis. In addition, the
combined results of these analyses suggested that several signaling pathways were affected by RanBPM down-regulation,
including ERK1/2, Wnt, Notch, and PI3K/Akt pathways. Lastly, analysis of selected target genes by quantitative RT-qPCR
confirmed the changes revealed by microarray. Several of the genes up-regulated in RanBPM shRNA cells encode proteins with
known oncogenic functions, such as the RON tyrosine kinase, the adhesion molecule L1CAM, and transcription factor
ELF3/ESE-1, suggesting that RanBPM functions as a tumor suppressor to prevent deregulated expression of these genes.
Altogether, these results suggest that RanBPM does indeed function to regulate many genomic events that regulate embryonic,
tissue, and cellular development as well as those involved in cancer development and progression. (AJCR0000135).
Keywords: RanBPM, ERK, Wnt, Notch, microarray, cancer, development
Address all correspondence to:
Dr. Caroline Schild-Poulter
Dr. Robarts Research Institute
100 Perth Drive, London
Ontario, N6A 5K8, Canada.
Tel: 519-663-5777 (ext 24164); Fax: 519-931-5252
E-mail: cschild-poulter@robarts.ca
Original Article
RanBPM expression regulates transcriptional pathways involved in
development and tumorigenesis
Elnaz Atabakhsh, Jean H Wang, Xu Wang, David E Carter, Caroline Schild-Poulter
Robarts Research Institute and Department of Biochemistry, Schulich School of Medicine & Dentistry, Western University,
London, Ontario, N6A 5K8, Canada
Received July 5, 2012; accepted August 9, 2012; Epub August 20, 2012; Published September 15, 2012
Abstract: RanBPM is a ubiquitous protein that has been reported to regulate several cellular processes through interactions
with various proteins. However, it not known whether RanBPM may regulate gene expression patterns. As it has been shown that
RanBPM interacts with a number of transcription factors, we hypothesized that it may have wide ranging effects on gene
expression that may explain its function. To test this hypothesis, we generated stable RanBPM shRNA cell lines to analyze the
effect of RanBPM on global gene expression. Microarray analyses were conducted comparing the gene expression profile of
Hela and HCT116 RanBPM shRNA cells versus control shRNA cells. We identified 167 annotated genes significantly up- or
down-regulated in the two cell lines. Analysis of the gene set revealed that down-regulation of RanBPM led to gene expression
changes that affect regulation of cell, tissue, and organ development and morphology, as well as biological processes
implicated in tumorigenesis. Analysis of Transcription Factor Binding Sites (TFBS) present in the gene set identified several
significantly over-represented transcription factors of the Forkhead, HMG, and Homeodomain families of transcription factors,
which have previously been demonstrated as having important roles in development and tumorigenesis. In addition, the
combined results of these analyses suggested that several signaling pathways were affected by RanBPM down-regulation,
including ERK1/2, Wnt, Notch, and PI3K/Akt pathways. Lastly, analysis of selected target genes by quantitative RT-qPCR
confirmed the changes revealed by microarray. Several of the genes up-regulated in RanBPM shRNA cells encode proteins with
known oncogenic functions, such as the RON tyrosine kinase, the adhesion molecule L1CAM, and transcription factor
ELF3/ESE-1, suggesting that RanBPM functions as a tumor suppressor to prevent deregulated expression of these genes.
Altogether, these results suggest that RanBPM does indeed function to regulate many genomic events that regulate embryonic,
tissue, and cellular development as well as those involved in cancer development and progression. (AJCR0000135).
Keywords: RanBPM, ERK, Wnt, Notch, microarray, cancer, development
Address all correspondence to:
Dr. Caroline Schild-Poulter
Dr. Robarts Research Institute
100 Perth Drive, London
Ontario, N6A 5K8, Canada.
Tel: 519-663-5777 (ext 24164); Fax: 519-931-5252
E-mail: cschild-poulter@robarts.ca
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