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Signaling pathways that regulate cellular senescence

  • Author(s): Freund, Adam Mark
  • Advisor(s): Campisi, Judith
  • Collins, Kathleen
  • et al.
Abstract

Chronic inflammation is associated with aging and plays a causative role in several age-related diseases such as cancer, atherosclerosis, and osteoarthritis. Studies have shown that cellular senescence, a tumor suppressive stress response that is also associated with aging, entails a striking increase in the secretion of pro-inflammatory proteins, termed the senescence-associated secretory phenotype (SASP), which might be an important contributor to chronic inflammation. Little is known about pathways that regulate the SASP, or how those pathways overlap with the pathways that regulate the senescence growth arrest, such as p53 and p16INK4A. We previously showed that DNA damage response (DDR) signaling is essential but not sufficient to establish and maintain the SASP. Additionally, p53, while required for senescence growth arrest, is not required for the SASP and in fact restrains the phenotype.

In this dissertation, I delineate a crucial pathway for regulating the SASP and its relationship to the classic DDR and p53. I show, in normal human fibroblasts, that senescence-inducing stimuli such as ionizing radiation or oncogenic RAS activate p38MAPK with kinetics that parallel the development of the SASP. p38MAPK was required for the majority of SASP expression, and constitutive activation of p38MAPK was sufficient to induce a robust SASP. Moreover, p53 restrained p38MAPK activation such that p38MAPK was more active in p53-deficient cells, and the amplified SASP caused by p53 deficiency was p38MAPK dependent. Further, p38MAPK activation was independent of the DDR and constitutive p38MAPK activation induced a SASP without inducing DDR signaling. Mechanistically, p38MAPK induced the SASP at the mRNA level by increasing NF-κB transcriptional activity. These findings assign p38MAPK a novel role in SASP regulation - one that is independent of previously described pathways.

I also examined how the p38MAPK/NF-κB pathway affected the senescence growth arrest. p38MAPK was required for oncogene-induced growth arrest, however it was not required for DNA damage-induced growth arrest, and NF-κB was not required for growth arrest in either context or for p38MAPK-induced senescence. Thus, p38MAPK regulates the SASP but not growth arrest via NF-κB, demonstrating a bifurcation in the growth arrest/SASP pathways downstream of p38MAPK. These findings demonstrate how the SASP and growth arrest can be independently regulated, suggesting possibilities for mitigating the deleterious effects of the SASP without adversely affecting the tumor suppressive growth arrest. Additionally, these data have implications for our understanding of growth arrest regulation in oncogenic backgrounds.

Lastly, I identified lamin B1 loss as a novel biomarker of senescence that is independent of other senescence regulatory pathways and may serve as a useful tool for identifying senescent cells in multiple contexts.

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