Src family kinase inhibitor PP2 accelerates differentiation in human intestinal epithelial cells

Abstract

The proto-oncogene Src is an important protein tyrosine kinase involved in signaling pathways that control cell adhesion, growth, migration and survival. Here, we investigated the involvement of Src family kinases (SFKs) in human intestinal cell differentiation. We first observed that Src activity peaked in early stages of Caco-2/15 cell differentiation. Inhibition of SFKs with PP2, a selective SFK inhibitor, accelerated the overall differentiation program. Interestingly, all polarization and terminal differentiation markers tested, including sucrase-isomaltase, lactase-phlorizin hydrolase and E and Li-cadherins were found to be significantly up-regulated after only 3 days of treatment in the newly differentiating cells. Further investigation of the effects of PP2 revealed a significant up-regulation of the two main intestinal epithelial cell-specific transcription factors Cdx2 and HNF1α and a reduction of polycomb PRC2-related epigenetic repressing activity as measured by a decrease in H3K27me3, two events closely related to the control of cell terminal differentiation in the intestine. Taken together, these data suggest that SFKs play a key role in the control of intestinal epithelial cell terminal differentiation.

Benzyl butyl phthalate decreases myogenic differentiation of endometrial mesenchymal stem/stromal cells through miR-137-mediated regulation of PITX2

“…Our results found that TLR2 and SRC were dysregulated in response to BBP treatment. This finding is consistent with previous studies, we found TLR2 gene related to immune 24 , and SRC which has been described to be related with epithelial cell differentiation 23 . A previous study has investigated the alteration in the gene expression following phthalate treatment in which exposure to this compound caused a dys-regulation in the expression of many genes, including apoptosis-, cell proliferation-, and immune response- related genes 36, 37 .…”

“…In previous studies, PITX2, a homeodomain transcription factor, is essential for normal development and differentiated of tissue 20, 21 . Recent studies have reported that SRC plays a role in signal pathways involved in cell proliferation, growth, survival osteoclast and intestinal epithelial cell differentiation 22, 23 . In addition, TLR2 play a central role in the innate immune system and is associated with B cell differentiation 24 .…”

Histone Deacetylase Inhibition Impairs Normal Intestinal Cell Proliferation and Promotes Specific Gene Expression

“…After dissection, intestinal samples (ileum and proximal colon) were immediately snap frozen in liquid nitrogen and homogenized in 1X Laemmli buffer with a tissue blender. Cells were scraped in 1X Laemmli buffer as previously described [Seltana et al, ]. After sonication, samples were centrifuged and supernatants were stored at −80°C until use.…”

Epigenetics in Intestinal Epithelial Cell Renewal

“…Our laboratory has recently found that inhibition of Src family kinases (SFKs) is associated with a decrease of H3K27me3 mark as well as a significant increase in intestinal cell differentiation markers. These data suggest that SFKs, which are negative regulators of the differentiation of intestinal cells, could act upstream of the PRC2 complex (Seltana et al, ). A detailed characterization of these SFK regulatory mechanisms needs further investigation.…”