| Popis: |
Background: The target of rapamycin (TOR), a major pathway for the regulation of cell growth and proliferation is conserved from yeast to humans. Fission yeast contains two tor complexes, TORC1 is crucial for cell growth while TORC2 gets activated under stress conditions. Pop3/Wat1, a mammalian Lst8 ortholog is an important component of both TOR complexes and has been implicated in the oxidative stress response pathway. Results: The genetic interaction analysis have revealed a synthetic lethal interaction of wat1 with tor2-287 mutant cells. The co-immunoprecipitation studies revealed a physical interaction of Wat1 with the TORC1 components such as Tor2, Mip1, and Tco89. In addition, the mutant Wat1 protein was unable to interact with these proteins. In the absence of Wat1, the cells arrest at G1 phase with reduced cell size at non-permissive temperature reminiscent of tor2-287 mutant phenotype. Similarly, inactivation of Wat1 results in the failure of TORC1 mediated phosphorylation of Psk1 and Rps602, leading to dysregulation of amino acid permeases and delocalization of Gaf1, a DNA binding transcription factor. Additionally, over-expression of rhb1 suppresses the glycerol and KCl sensitivity of wat1Δ and wat1-17 mutant cells suggesting the suppression of osmotic stress response. Conclusion: We proposed that the Wat1/Pop3 is very critical component of TORC1 complex and hence the inactivation of wat1 impaired the downstream signalling of TORC1 pathway. Considering the roles of mLst8, a mammalian ortholog of Wat1 in the tumor progression, novel therapeutic approaches can be utilized to target Wat1/mLst8 that could impede the tumor progression. |
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