Mechanism of the cell death induced by joint activation of p53 and ISR networks

Annotation:

TP53, which encodes transcription factor p53, is the most frequently mutated tumor suppressor gene in human cancers. Various types of cellular stress induce p53, which then transactivates a broad range of genes involved in numerous anti-cancer programs, including cell cycle arrest, DNA repair, senescence, and apoptosis. However, in most cancer types, targeted induction of p53 by small molecule inhibitors of MDM2 (a key upstream negative regulator) leads to a reversible proliferation block, while the therapeutically desirable elimination of cancer cells by apoptosis remains limited.

Recently, our laboratory identified a novel regulatory mechanism within the p53 network responsible for restraining the apoptotic response upon p53 activation. In this scenario, p53 activity maintains the eukaryotic translation initiation factor eIF2a in a dephosphorylated and fully functional state. Pharmacologically severing this negative feedback loop with eIF2a inhibitors leads to rapid onset of apoptosis in cancer cells in vitro and results in stalled tumor growth and improved animal survival in vivo. Cell death upon dual activation of the p53 and ISR pathways is accompanied by induction of transcriptional programs governed by p53, ATF4, and XBP1. We hypothesize that p53, ATF4, and XBP1 co-regulate a conserved transcriptional program required for cell death triggered by combination of MDM2 and eIF2a inhibitors. To test this hypothesis, PhD candidate will pursue following aims:

1. To map p53, ATF4, and XBP1 occupancy in multiple CRC cell lines.
2. To use genome-wide CRISPR screens and RNA-seq data in matching cell lines to identify and validate mediators of cell death induced by joint activation of the p53 and ISR pathways.

Funding of the research:

GACR project 25-18368S, internal sources of the laboratory.

Information on funding PGS positions:

The program requires that all PhD students have some means of financial support of min. 25 000 CZK per month. This is often a combination of various sources (grants, scholarship etc.)

Requirements for the student according to the Doctoral Board:

The student's minimum publication activity within the course of study is one first-author publication with an IF value above the median in the field or 2 first-author publications in journals with an IF value in the 3rd quartile in the field (Q3). A condition for successful completion of the studies is also a foreign internship of at least 1 month, which is an inseparable part of the studies. As part of their studies, students will also participate in the teaching.

Additional reading:

https://pmc.ncbi.nlm.nih.gov/articles/PMC9715646/