Comparisons of cellular senescence pathways: between human and mouse fibroblasts and between various oncogenes

Alyssa Lee Kennedy

doi:10.17918/00007487

Cellular senescence is a state of permanent growth arrest that is triggered in response to various cell stressors. These stressors include short telomeres (replicative senescence), DNA damage or activated oncogenes (oncogene-induced senescence). In the presence of these potentially tumor-promoting genetic aberrations, the cell permanently exits the cell cycle rather than continue to divide. In so doing, senescence serves as a tumor suppression mechanism. A critical component of the senescence program is formation of facultative heterochromatin, termed senescence associated heterochromatin foci (SAHF). These SAHF are thought to reinforce the senescence arrest by silencing proliferation-promoting genes. HIRA, a histone chaperone whose activity is regulated by WNT signaling, has been shown to be important for regulating formation of SAHF during senescence. In this thesis work, I set out to determine whether mouse cells have a functional HIRA mediated heterochromatin-formation pathway. We find that in mouse embryo fibroblasts (MEFs), the HIRA mediated heterochromatin pathway does not function as it does in human fibroblasts. In both mouse dermal fibroblasts with shortened telomeres or MEFs transduced with an activated RAS oncogene, there is no evidence of HIRA activation or SAHF formation. These results may contribute to the differences in tumor suppression capabilities between mouse and human. The second portion of this thesis work addresses differences between various oncogenes in their ability to induce senescence. Using primary human fibroblasts, I find that PI3K/AKT pathway activation differs from RAS activation in its ability to induce senescence. Specifically, activation of PI3K/AKT pathway induces a less robust growth arrest, does not induce formation of SAHF, does not lead to increased secretion of inflammatory mediators and also does not induce DNA damage. Additionally, we find that AKT is capable of antagonizing the effects of activated RAS on heterochromatin formation and HIRA activation. Finally, in an in vivo mouse model of RAS-induced senescence in the mouse pancreas, we show that PI3K pathway activation leads to abrogation of RAS-induced senescence and, consequently, rapid tumorigenesis. These findings elucidate critical differences between oncogenes in their ability to induce senescence, and also demonstrate a novel form of oncogene cooperation between these two potent oncogenic pathways.

Comparisons of cellular senescence pathways: between human and mouse fibroblasts and between various oncogenes

Files and links (1)

Abstract

Metrics

Details

Comparisons of cellular senescence pathways: between human and mouse fibroblasts and between various oncogenes

Files and links (1)

Abstract

Metrics

Details

Drexel University Social media