Genetic and hypoxic effects on germline tumor development in caenorhabditis elegans

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Udaya Sree Datla (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: The process of differentiation of stem cells to committed, progenitor specific cell types is well studied but the reverse process of the dedifferentiation of these committed cells back to the undifferentiated state still remains a major challenge in stem cell biology. In my project, we studied some of the major regulators of the dedifferentiation process taking C. elegans germline model system. In C. elegans, the germline stem cells at the distal end that initially divide mitotically then enter meiosis and differentiate into gametes as they progress towards the proximal end. In the first part of my project, we proposed that the Ras-ERK MAPK signaling activated by the removal of two negative regulators, PUF-8 RNA-binding protein and LIP-1 dual specificity phosphatase, plays an important role in controlling the dedifferentiation of secondary spermatocytes at the proximal end to a more undifferentiated, multipotent state forming proximal germline tumor. Further, by RNAi screening, the RSKN-1/P90RSK, a downstream effector of MPK-1/ERK was identified to be critical for this (already published). As a continuation of my project, next, the HIF-1 (Hypoxia inducible factor-1) transcription factor that plays a key role in oxygen homeostasis during hypoxic conditions for the survival of the organism has been studied for its pronounced effect on this dedifferentiation-mediated tumorigenesis process. We found that under hypoxic conditions or under the conditions that mimic hypoxia (by exposing the worms to cobalt chloride, a chemical inducer of hypoxia), the activation of HIF-1 inhibits dedifferentiation-mediated tumorigenesis in puf-8\; lip-1 mutant germline, probably through Ras-ERK MAPK signaling. Besides focusing on the effect of hypoxia on dedifferentiation-mediated tumorigenesis, we also studied the effect of hypoxia on glp-1(ar202), also called glp-1(gf) gain-of-function mutant - used to study GLP-1/Notch-mediated tumorigenesis where the tumor development occurs via a different pathway where the meiotic entry of germline stem cells are inhibited and instead self-renews and in the process of self-renewal forms the tumor cell-like cells. Interestingly, the activation of HIF-1 by either genetic manipulation or cobalt chloride treatment also inhibited GLP-1/Notch-mediated tumorigenesis. It suggests that there might be a common mechanism underlying the action of HIF-1 in both dedifferentiation-mediated and GLP-1/Notch-mediated germline tumors.

Additional Information

Publication

Thesis

Language: English

Date: 2023

Subjects

Oncology;Biology, Cellular;Caenorhabditis elegans;Dedifferentiation;Hypoxia;MAPK signaling;PUF RNA binding protein;Tumorigenesis;Cellular biology;C. elegans

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