Regulation of TIF1β Phosphorylation in Colorectal Cancer Progression
Date Issued
2014
Date
2014
Author(s)
Shen, Tzu-Wei
Abstract
Dynamic state of post-translational modifications has been postulated to involve in a wide range of processes in cancer. Notably, dysregulating the balance between kinases and phosphatases leads to change protein phosphorylation status which has amply reported in cancer progression. Protein phosphatase 4 (PP4) is a serine/threonine phosphatase and is highly expressed in terminal stage of breast and lung cancer. However, the function of PP4 in tumor progression remain unclear. PP4 directly acts on serine 473 of Transcription Intermediary Factor 1 beta (TIF1β) phosphorylation during DNA damage response. TIF1β is an intermediary factor of transcription and epigenetic modulator of gene expression in several physiological processes including embryonic development and cell differentiation as well as in establishment and/or progression of some cancers. Interestingly, serine 473 residue of TIF1β affects the binding between TIF1β and heterochromatin protein 1 (HP1) which could regulate chromatin remodeling and epigenetic modulation. In this study, we used human colorectal cancer to investigate the molecular mechanisms regulating phosphorylation/de-phosphorylation of TIF1β through PP4 and its specific kinase in tumor progression. Comparison of immunohistochemistry (IHC) data on different differentiation grades of colon cancer showed low expression of phosphorylated TIF1β which were consistent with high PP4C expression on high grade which provides a link that PP4 may be involved in de-phosphorylation of TIF1β in tumor progression. Our IHC data on basal layer of oral epithelium and crypt region of intestinal epithelium have shown that the phosphorylated TIF1β is an event closely correlated with cellular proliferation and differentiation. In addition, phosphorylated TIF1β was found to be highly expressed in mouse intestine adenoma and oncogenic HRas-induced invasion region indicating that phosphorylated TIF1β is involved in tumor progression. I used 3D culture model with c-Jun/JunB mutants to compare cells in different potentials of differentiation, phosphorylated TIF1β has only been shown in the differentiation proficient cells but not in the differentiation deficient cells. It suggested phosphorylated TIF1β is correlated with cellular differentiation-dependent proliferation to further involve in tumor progression. Furthermore, I confirmed phosphorylated TIF1β could be induced by EGF through RAS-MEK-ERK signaling pathway and ERK-1/2 may be one of the possible kinases. Based on experimental data, I suggest that the phosphorylated TIF1β may be involved in cellular proliferation and differentiation as well as tumor progression through homeostatic balance between PP4 and its kinase.
Subjects
Colorectal Cancer
Phosphorylation
EGF signaling
SDGs
Type
thesis
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