NatB regulates Rb mutant cell death and tumor growth by modulating EGFR/MAPK signaling through the N-end rule pathways
Autoři:
Zhentao Sheng aff001; Wei Du aff001
Působiště autorů:
Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, United States of America
aff001
Vyšlo v časopise:
NatB regulates Rb mutant cell death and tumor growth by modulating EGFR/MAPK signaling through the N-end rule pathways. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008863
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008863
Souhrn
Inactivation of the Rb tumor suppressor causes context-dependent increases in cell proliferation or cell death. In a genetic screen for factors that promoted Rb mutant cell death in Drosophila, we identified Psid, a regulatory subunit of N-terminal acetyltransferase B (NatB). We showed that NatB subunits were required for elevated EGFR/MAPK signaling and Rb mutant cell survival. We showed that NatB regulates the posttranscriptional levels of the highly conserved pathway components Grb2/Drk, MAPK, and PP2AC but not that of the less conserved Sprouty. Interestingly, NatB increased the levels of positive pathway components Grb2/Drk and MAPK while decreased the levels of negative pathway component PP2AC, which were mediated by the distinct N-end rule branch E3 ubiquitin ligases Ubr4 and Cnot4, respectively. These results suggest a novel mechanism by which NatB and N-end rule pathways modulate EGFR/MAPK signaling by inversely regulating the levels of multiple conserved positive and negative pathway components. As inactivation of Psid blocked EGFR signaling-dependent tumor growth, this study raises the possibility that NatB is potentially a novel therapeutic target for cancers dependent on deregulated EGFR/Ras signaling.
Klíčová slova:
Cell death – Cloning – Drosophila melanogaster – EGFR signaling – Eyes – MAPK signaling cascades – RNA interference – Ubiquitin ligases
Zdroje
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