Elucidating the role of the African-centric p47s variant of TP53 in metabolism and ferroptosis / Keerthana Gnanapradeepan.

Format:

Book

Thesis/Dissertation

Author/Creator:

Gnanapradeepan, Keerthana, author.

Contributor:

Murphy, Maureen E., degree supervisor.

University of Pennsylvania. Department of Biochemistry and Molecular Biophysics, degree granting institution.

Language:

English

Subjects (All):

Oncology.

Biochemistry.

Cellular biology.

Biochemistry and Molecular Biophysics--Penn dissertations.

Penn dissertations--Biochemistry and Molecular Biophysics.

Local Subjects:

Oncology.

Biochemistry.

Cellular biology.

Biochemistry and Molecular Biophysics--Penn dissertations.

Penn dissertations--Biochemistry and Molecular Biophysics.

Genre:

Academic theses.

Physical Description:

1 online resource (132 pages)

Contained In:

Dissertations Abstracts International 82-11B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2021.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

The tumor suppressor gene TP53 is the most frequently mutated gene in cancer and plays a key role in mediating several processes that are critical for preventing tumor formation and progression. Known as the guardian of the genome, p53 regulates hundreds of genes involved in various pathways such as apoptosis, cell cycle arrest and senescence. In recent years, the role of p53 in metabolism, redox state and ferroptosis has begun to emerge. Our lab has identified an African-specific polymorphic variant of p53 that encodes a serine residue instead of a proline at amino acid 47 (hereafter S47) and predisposes carriers to cancer. The S47 variant is impaired for tumor suppression and ferroptosis, and S47 cells have an altered redox state. We sought to use the tumor prone S47 model as a tool to better understand the role of p53 in tumor suppression. Our results demonstrate that mice carrying the S47 variant have greater metabolic efficiency compared to those with WT p53, along with increased mTOR activity. This difference in mTOR stems from an impaired protein-protein interaction that occurs in S47, ultimately due to a difference in cellular redox state. We next identified PLTP as a p53 target gene that shows decreased transactivation in the S47 variant and mediates ferroptosis resistance by enhancing lipid storage in HepG2 cells. Taken together, this work sheds light on the emerging roles p53 plays in tumor suppression, metabolism and ferroptosis. It also provides a better understanding of an ethnic genetic variant of p53. We expect this work will enable better personalized medicine approaches and therapeutic options for people who carry this variant.

Notes:

Source: Dissertations Abstracts International, Volume: 82-11, Section: B.

Advisors: Murphy, Maureen E.; Committee members: Kathryn Wellen; Xiaolu Yang; Zachary Schug; Donna George.

Department: Biochemistry and Molecular Biophysics.

Ph.D. University of Pennsylvania 2021.

Local Notes:

School code: 0175

ISBN:

9798738641848

Access Restriction:

Restricted for use by site license.

This item must not be sold to any third party vendors.