Carla Finkielstein to speak about circadian rhythm mechanisms and cancer treatment at Virginia Tech Life Science Seminar – Virginia Tech Daily

From: Fralin Life Sciences Institutue

Carla Finkielstein, director of the Molecular Diagnostics Lab at the Fralin Biomedical Research Institute at VTC and an associate professor of biological sciences in Virginia Tech’s College of Science, will speak at the Virginia Tech Life Science Seminar (VTLSS) on Friday, Sept. 3, at 12:00 p.m. VTLSS is a university-wide seminar series funded by the Fralin Life Sciences Institute at Virginia Tech.

When: Friday, Sept. 3, 2021 at 12:00 p.m.

Where: Fralin Hall Auditorium

Host: VTLSS Committee 

Title: “Exploiting molecular circadian crosstalk mechanisms for cancer treatment”

Abstract: “Previously, cancer treatment modalities relied primarily on chemotherapeutic agents; nowadays, advances in rationally-designed drugs and targeted therapies have enabled the manipulation of cancer-specific molecules and cancer regulators that are frequently mutated and globally identified in various cancers. Regardless the approach, the objective has always been to attenuate, eliminate, or control the neomorphic activity of a given target driver mutation. In this context, a distinct dimension that needs to be considered relates to the spatial-temporal distribution of a given target molecule in the cell and whether this feature could be therapeutically exploited.

Our findings show that PERIOD 2 (PER2), a core clock component directly involved in the generation and maintenance of circadian rhythms, directly interacts with the tumor suppressor p53 and its negative regulator, the proto-oncogene mouse double minute 2 homolog (MDM2). In unstressed conditions, binding of PER2 to p53 controls p53’s stability, transcriptional activity, and time-of-day-dependent nuclear-cytoplasmic shuttling, thus, generating an asymmetric distribution of each protein in different cellular compartments. Binding of PER2 to the E3-ligase MDM2 also occurs in the absence of p53, leading to PER2 ubiquitination and degradation in a process that directly influences the circadian period length of the cell. Interestingly, TP53, PER2, and MDM2 missense mutation data, obtained from human tumor samples (n>1,100) and recapitulated in vitro, showed that various single-nucleotide mutations functionally disrupt the localization, formation, stability, and/or distribution of either PER2:p53 or PER2:MDM2 complexes in the cell.

This finding goes along with the absence of a normal circadian rhythm oscillation in primary cells bearing those mutations. As a result, we advocate for a more comprehensive study of treatment modalities that take into consideration the direct role of circadian components on the modulation of the tumor suppressor’s function.”

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