Identification of a tumour suppressor network opposing nuclear Akt function

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• The proto-oncogene AKT is activated in many human cancers, often due to PTEN loss.
• Activated AKT at the cell membrane phosphorylates nuclear targets like FOXO transcription factors, but its nuclear role in tumorigenesis is unclear.

Purpose of the Study:

• To investigate the role of the PML tumor suppressor in regulating nuclear AKT activity and its impact on tumorigenesis.

Main Methods:

• Utilized a mouse model with Pten-heterozygous mutations to study the effects of Pml loss.
• Investigated the localization and activity of AKT and PP2a in Pml nuclear bodies.
• Assessed the impact of Pml deficiency on FOXO transcription factor activity and downstream targets.

Main Results:

• Pml loss accelerated tumor onset, incidence, and progression in Pten-heterozygous mice.
• Pml deficiency led to prostate tumorigenesis and female sterility, mimicking Foxo3a knockout phenotypes.
• Pml recruits AKT phosphatase PP2a and pAKT into nuclear bodies, and Pml-null cells show impaired PP2a activity, leading to nuclear pAKT accumulation.
• Reduced Pml levels resulted in inactivation of Foxo3a-mediated transcription of Bim and p27(kip1).

Conclusions:

• PML acts as a nuclear tumor suppressor by inactivating nuclear AKT.
• PML orchestrates a nuclear network to control nuclear AKT, emphasizing the importance of AKT compartmentalization in cancer.
• PML's function highlights potential therapeutic strategies targeting AKT localization in cancer treatment.