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P53 ISOFORMS AND CELLULAR SENESCENCE IN BRAIN CANCER AND RADIOTHERAPY

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posted on 14.12.2020, 22:27 by Jessica Ann Beck
In addition to the canonical full-length p53 (FLp53), the TP53 gene produces twelve protein isoforms through alternative RNA splicing or initiation of transcription and translation. Two of
these isoforms, D133p53a and p53b, have been identified as endogenous regulators of cellular senescence. Cellular senescence is a durable cell cycle arrest that inhibits the continued replication of aged and DNA-damaged cells. This process is a critical mechanism of tumor suppression that
prevents initiation and malignant progression and has been leveraged to treat cancers including glioblastoma. However, removal of senescent cells by macrophages is needed to restore tissue homeostasis. This process is impacted by a variety of factors. For example, senescent cells accumulate in aged individuals and can promote chronic inflammation and disease through the senescence-associated secretory phenotype (SASP). As the global population ages, it will become more critical to understand the function of cellular senescence in disease. Targeting senescent cells, either through elimination (senolysis) or reprogramming, may have potential therapeutic value in individuals with a high senescent cell burden. Aged or DNA-damaged cells adopt a senescence-associated p53 isoform profile characterized by reduced expression of D133p53a and increased expression of p53b. Critically, restoration of D133p53a rescues cells from senescence and enhances DNA repair. Targeting p53
isoforms may represent a mechanism by which cells can be reprogrammed. A thorough understanding of the contexts in which senescent cells maintain beneficial or harmful roles is
critical to developing senescence therapeutics in cancer and aging.

History

Degree Type

Doctor of Philosophy

Department

Comparative Pathobiology

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Curtis Harris

Advisor/Supervisor/Committee co-chair

Margaret Miller

Additional Committee Member 2

Susan Mendrysa

Additional Committee Member 3

Mark Simpson

Additional Committee Member 4

Jose Ramos-Vara

Licence

Exports

Licence

Exports