Details

Autor(en) / Beteiligte

• Zerlanko, Brad Joseph

Titel

Regulation of Proliferation and Oxidative Stress by Tgif1 and TGFβ

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2011

Link zum Volltext

• ProQuest

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Tgif1 is a transcriptional co-repressor that is best known for limiting transforming growth factor β (TGFβ) responsive gene expression. TGFβ signaling regulates the cell cycle by inducing a G1 cell cycle arrest. It has recently been shown that mouse embryonic fibroblasts (MEFs) lacking Tgif1 are defective in cell cycling but the cause of this remains unknown. The goal of my work has been to determine the role Tgif1 plays in sustaining cell growth. In the absence of Tgif1, we observe a flat morphology, increase in ploidy and beta galactosidase activity that are characteristic of a permanent exit from the cell cycle known as cellular senescence. Further, Tgif1 null MEFs have elevated levels of DNA damage. Growth under physiological oxygen conditions can reduce the amount of DNA damage repair foci and partially rescue the growth of Tgif1 null MEFs. Also, Tgif1 null MEFs are more sensitive to low levels of TGFβ signaling that can induce premature senescence in wild type MEFs. The following model has emerged: In the absence of Tgif1, cells are more sensitive to both low level TGFβ signaling and DNA damage due to hyperoxic stress, which ultimately result in premature senescence. A common cause of DNA damage is reactive oxygen species (ROS). Our research provides evidence that MEFs and normal mouse liver (NMuLi) cells lacking Tgif1 accumulate ROS, suggesting a novel role for Tgif1 in regulating oxidative stress that could also provide insight into how Tgif1 maintains cellular proliferation.