SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in...

Area of Science:

• Molecular Biology
• Cancer Biology
• Cellular Signaling

Background:

• Ribosomal proteins (RPs) are known regulators of the MDM2-p53 pathway.
• Upstream regulators of RPs, particularly in the context of cancer, remain largely uncharacterized.

Purpose of the Study:

• To identify novel upstream regulators of RPs involved in the MDM2-p53 pathway.
• To elucidate the role of Spindlin 1 (SPIN1) in cancer cell regulation via the MDM2-p53 axis.

Main Methods:

• Identification of SPIN1 as a binding partner of human RPL5/uL18.
• Experimental ablation of SPIN1 in human cancer cells.
• Analysis of p53 activation, cell growth, clonogenic ability, and apoptosis.
• Investigation of the mechanistic interaction between SPIN1, uL18, MDM2, and p53.
• Correlation analysis with cancer genomic databases.

Main Results:

• SPIN1 directly binds to human RPL5/uL18.
• SPIN1 ablation leads to p53 activation, suppressed cell growth, reduced clonogenic potential, and induced apoptosis in cancer cells.
• SPIN1 sequesters uL18 in the nucleolus, preventing its interaction with MDM2 and alleviating uL18-mediated inhibition of MDM2 ubiquitin ligase activity towards p53.
• SPIN1 deficiency increases ribosome-free uL18 and uL5 (human RPL11), which are crucial for p53 activation.
• SPIN1 is overexpressed in multiple human cancers and correlates with poor patient prognosis.

Conclusions:

• SPIN1 acts as a novel upstream regulator of the MDM2-p53 pathway by sequestering uL18.
• SPIN1's oncogenic properties stem from its negative regulation of uL18, leading to p53 inactivation.
• Targeting SPIN1 may represent a therapeutic strategy for cancers exhibiting its overexpression.