Abstract
BackgroundWDR13 is a member of the WD repeat protein family and is expressed in several tissues of human and mice. Previous studies in our laboratory showed that the lack of this gene in mice resulted in mild obesity, hyperinsulinemia, enhanced beta cell proliferation and protection from inflammation. However, the molecular mechanism of WDR13 action is not well understood.MethodsIn the present study, we used AOM/DSS to induce colitis-mediated colorectal tumor after establishing expression of Wdr13 gene in colon. Further, we have used human colon cancer cell lines, HT29 and COLO205, and mouse primary embryonic fibroblast to understand the molecular mechanism of WDR13 action.ResultsWe observed that mice lacking Wdr13 gene have reduced number of tumors and are more susceptible to DSS-induced colon ulcers. We also show that WDR13 is a part of multi protein complex c-Jun/NCoR1/HDAC3 and it acts as a transcriptional activator of AP1 target genes in the presence of JNK signal. Consistent with in vitro data, we observed reduced expression of AP1 target genes in colon after AOM/DSS treatment in Wdr13 knockout mice as compared to that in wild type.ConclusionMice lacking Wdr13 gene showed reduced expression of AP1 target genes and protection from colitis-induced colorectal tumors.
Highlights
WD repeat domain 13 (WDR13) is a member of the WD repeat protein family and is expressed in several tissues of human and mice
We show that WDR13 acts as a transcriptional activator of AP1 target genes in the presence of Jun N-terminal kinase (JNK) signal
Consistent with the genotypes of the cells, we found 53.0 kDa and 43.0 kDa protein isoforms from Wdr13+/0 Mouse embryonic fibroblasts (MEF) and these were absent in Wdr13-/0 MEFs (Fig. 1b)
Summary
WDR13 is a member of the WD repeat protein family and is expressed in several tissues of human and mice. Cell death and differentiation are basic processes of eukaryotic organisms. These processes are regulated by numerous signals including growth factors, cytokines and extracellular signals, which decide the fate between cell cycle progression and apoptosis through cytoplasmic signalling cascades to the nucleus [1,2,3]. Non-canonical Wnt. The proto-oncogene, c-Jun, belongs to the AP1 group of transcription factors [10, 11]. C-Jun heterodimerizes and forms active transcription factors with Fos and ATF families of proteins [12]. AP1 activity, in part, is regulated by phosphorylation of c-Jun at serine residues 63 and 73 and threonine residues 91 and 93 by JNK [13]. c-Jun binds the co-repressor complex NCoR1/
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