P53 pathway

Question 1

How is P53 regulated in normal cells?

Answer 1

Mdm2/Mdmx heterodimer is bound to P53. Mdm2 continuesly poly-ubiquitinates P53 leading to its degradation. In stress conditions, P53 gets activated and relocates to the nucleus to start transcription of downstream genes. That cause growth inhibition or mediate apoptosis. P53 also initiates transcription of MDM2 -> negative feedback.

Question 2

How is P53 activated upon oncogene signaling?

Answer 2

Loss of RB1 leads to expression of E2F. E2F initiates transcription of P14ARF. P14ARf interacts with MDM2 ininhibiting the ubiqutin-ligase activity, and leading to decreas of binding efficacy to P53.