The Cancer Specific Ubiquitin Ligase MAGE-A3/6-TRIM28 Drives Tumorigenesis by Ubiquitination and Proteasomal Degradation of AMPK

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dc.contributor.advisorYu, Hongtaoen
dc.contributor.committeeMemberLevine, Bethen
dc.contributor.committeeMemberWhite, Michael A.en
dc.contributor.committeeMemberPotts, Patrick Ryanen
dc.creatorPineda, Carlos Tyleren
dc.date.accessioned2018-01-04T21:09:36Z
dc.date.available2018-01-04T21:09:36Z
dc.date.created2015-12
dc.date.issued2015-08-27
dc.date.submittedDecember 2015
dc.date.updated2018-01-04T21:03:35Z
dc.description.abstractThe genes MAGE-A3 and MAGE-A6 (MAGE-A3/6) have a unique expression pattern in which they are normally expressed in the adult testis but are aberrantly expressed in cancer. It is known that when expressed in cancer, MAGE-A3/6 is a negative prognostic indicator and cancer cells are dependent on it for survival. Using the knowledge that MAGE-A3/6 binds and regulates the E3 ubiquitin ligase TRIM28, I investigated its biochemical role in cancer. I used unbiased methods to identify 19 novel substrates of MAGE-A3/6-TRIM28, including the known tumor suppressor AMPK. Ubiquitination of AMPK by MAGE-A3/6-TRIM28 induces its proteasomal degradation, thereby enhancing mTOR signaling and inhibiting autophagy within cells. Through this modulation of AMPK, MAGE-A3/6 is also able to act as an oncogene, inducing anchorage independent growth and the growth of tumors in vivo. Understanding the mechanism by which MAGE-A3/6 acts as an oncogene has revealed potential avenues of therapeutic intervention. Treatment of MAGE-A3/6 expressing cells with AMPK agonists reverses oncogenic properties in vitro. Ultimately, these studies have revealed how a germline protein functions in cancer and the potential points for therapeutic intervention.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1017760194
dc.identifier.urihttps://hdl.handle.net/2152.5/4447
dc.language.isoenen
dc.subjectAMP-Activated Protein Kinasesen
dc.subjectAntigens, Neoplasmen
dc.subjectNeoplasm Proteinsen
dc.subjectNeoplasmsen
dc.subjectUbiquitinationen
dc.subjectUbiquitin-Protein Ligasesen
dc.titleThe Cancer Specific Ubiquitin Ligase MAGE-A3/6-TRIM28 Drives Tumorigenesis by Ubiquitination and Proteasomal Degradation of AMPKen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCell Regulationen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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