Oncogenic MYC Induces the Impaired Ribosome Biogenesis Checkpoint and Stabilizes p53 Independent of Increased...

Area of Science:

• Cellular biology
• Cancer research
• Molecular oncology

Background:

• The role of MYC in p53 regulation and ribosome biogenesis is debated.
• MYC can either stabilize or destabilize p53 depending on ribosome biogenesis.
• Existing models conflict on how MYC affects ribosomal proteins (RP)L5 and RPL11 and their impact on p53.

Purpose of the Study:

• To investigate the precise mechanism by which MYC influences p53 stability.
• To elucidate the role of the impaired ribosome biogenesis checkpoint (IRBC) in MYC-driven processes.
• To determine the therapeutic potential of targeting the MYC-IRBC interaction in cancer.

Main Methods:

• MYC silencing and induction in cellular models.
• Analysis of p53 protein half-life and HDM2 dependency.
• Assessment of RPL5, RPL11, and 5S rRNA levels.
• Investigation of IRBC complex formation and HDM2 binding.

Main Results:

• MYC silencing decreased RPL5, RPL11, and 5S rRNA, leading to reduced p53 half-life in an HDM2-dependent manner.
• MYC induction increased ribosome biogenesis and p53 stabilization.
• Free RPL5/RPL11 levels remained unchanged, but IRBC complex binding to HDM2 increased significantly.
• Data suggest a tumor-suppressor role for the IRBC in response to MYC.

Conclusions:

• MYC oncogene activation triggers an intrinsic tumor-suppressor response via the IRBC.
• The IRBC complex, involving RPL5, RPL11, and 5S rRNA, plays a critical role in stabilizing p53 under MYC influence.
• Targeting the IRBC offers a promising therapeutic strategy for MYC-driven cancers.