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Title: Investigating the molecular mechanism of ERp29-regulated cell cycle arrest in breast cancer
Keywords: ERp29,cell cycle,cell cycle arrest,breast cancer
Issue Date: 28-Dec-2011
Citation: GAO DANMEI (2011-12-28). Investigating the molecular mechanism of ERp29-regulated cell cycle arrest in breast cancer. ScholarBank@NUS Repository.
Abstract: Endoplasmic reticulum protein 29 (ERp29) is a novel endoplasmic reticulum (ER) luminal protein and plays a critical role in protein unfolding and secretion. Recently, it was found that ERp29 is a novel tumor suppressor which drives the proliferative MDA-MB-231 breast cancer cells into a dormant state. However, the mechanism underlining this process is not fully understood. In this thesis, some aspects of the mechanism of how ERp29 induces tumor cell dormancy are studied. These studies provided evidence that overexpression of ERp29 induces breast cancer cell cycle arrest by modulating endoplasmic reticulum stress. Overexpression of ERp29 down regulates the expression of eIF2alpha, a key ER transcription factor, and up-regulates the cyclin-dependent kinase, p27kip1, a tumor suppressor. High expression of eIF2alpha was found in three proliferative breast cancer cell lines -- BT549, MDA-MB-231 and SKBR3, suggesting its potential as a marker of tumor aggressiveness. P58ipk was also markedly increased, and appeared to inhibit eIF2alpha phosphorylation. Silencing of eIF2alpha in ERp29-overexpressed MDA-MB-231 cells dramatically induces up-regulation of p27kip1. Data showed that the downstream target of eIF2alpha, cyclinD1, translocated into the cytoplasm of the ERp29-overexpressed MDA-MB-231 cells, in contrast to the accumulation of cyclinD1 inside the cell nuclei, in ERp29-silenced MCF7 cells. Using immunofluorescence imaging, the translocation of cyclinD1 into the cytoplasm was shown to be phosphorylation-dependent, as phosphorylated cyclinD1 also translocated to the cytoplasm in the ERp29-overexpressed MDA-MB-231 while in the ERp29-silenced MCF7, phosphorylated cyclinD1 accumulated inside the nuclei, which facilitates tumor growth.
Appears in Collections:Master's Theses (Open)

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