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Esra BRKL
 


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NETWORK ANALYSIS OF MTOR SIGNALING IN YEAST BY SYSTEM BIOLOGY APPROACHES REVEALS A POTENTIAL CROSSTALK WITH SPHINGOLIPID METABOLITES IN CANCER: GPRC5B AS A POTENTIAL DRUG TARGET
 
Mechanistic target of rapamycin (mTOR) signaling, a regulator of cell growth, is an important signaling pathway in cancer and has mTORC1 complex functioning as a nutrient/energy/redox sensor and controlling protein synthesis in the center. mTORC1 has many orthologues in other model organisms, including bakers yeast, Saccharomyces cerevisiae. In this study, first the reconstruction of mTOR signaling network in yeast was performed. Integration of gene ontology terms with protein-protein interaction data yielded a network comprised of 1568 nodes and 21455 edges. Then, the network was investigated in depth by scrutinizing possible key players in the mTOR (Tor1p) -CDK1 (Cdc28p) cancer biogenesis axis, via a linear path analysis with NetSearch algorithm. This procedure resulted in a denser biological, cancer-related network of 1510 nodes and 11353 edges. This dense network depicts the routes highly participating to the information flow in the network by identifying fundamental proteins for the proceeding of the signal transduction for studied Tor1p-Cdc28p pair. The integration of gene expression data of Tor1p deleted cells onto this dense network resulted in the responsive sub-network comprised of 382 nodes and 1285 edges, an interaction of modules overrepresented in response to mTOR repression, as in the case with rapamycin treatment. Modular analysis of this dense, responsive network gave insights about sphingolipid metabolism and particularly YNL194Cp, the yeast functional orthologue of mammalian GPRC5B, as another promising drug target in cancer treatment. ORCID NO: 0000-0002-1326-0608

Anahtar Kelimeler: network analysis, yeast, mTOR signaling, cancer, GPRC5B, systems biology