RNA-binding motif protein 10 inactivates c-Myc by partnering with ribosomal proteins uL18 and uL5

Area of Science:

• Molecular Biology
• Oncology
• Protein Biochemistry

Background:

• Lung adenocarcinoma (LUAD) is often driven by mutations in tumor suppressors like RNA-binding motif protein 10 (RBM10).
• The precise mechanisms by which mutant RBM10 loses its tumor-suppressive function in LUAD remain unclear.

Purpose of the Study:

• To investigate how wild-type and mutant RBM10 affect lung cancer cell growth.
• To elucidate the molecular mechanisms underlying RBM10's tumor suppressor activity and its inactivation by cancer-derived mutations.

Main Methods:

• Western blotting to assess protein levels and degradation.
• Co-immunoprecipitation assays to determine protein-protein interactions.
• Cell proliferation assays to evaluate tumor growth.

Main Results:

• Wild-type RBM10 suppresses lung cancer cell growth by directly binding to and promoting the ubiquitin-dependent degradation of c-Myc.
• Ribosomal proteins uL18 (RPL5) and uL5 (RPL11) enhance RBM10's inactivation of c-Myc through direct binding to RBM10.
• A common cancer-derived mutant, RBM10-I316F, cannot bind to uL18 and uL5, leading to failure in c-Myc inactivation and loss of tumor suppression.

Conclusions:

• RBM10 acts as a crucial repressor of c-Myc in lung cancer cells, a function dependent on its interaction with ribosomal proteins uL18 and uL5.
• Loss of RBM10's ability to interact with uL18/uL5 and subsequently inactivate c-Myc due to mutations promotes lung tumorigenesis.