The TP53 gene encodes the p53 protein. This 393-amino acid protein is a transcription factor that is regulated by phosphorylation and by its interaction with another phosphoprotein, the negative regulator Mdm2. In a normal cell, both proteins are unphosphorylated, which allows them to bind together. Mdm2 stimulates degradation of p53, and, as a result, the amount of p53 in the cell is low. When DNA damage occurs, p53 initiates a cascade of events leading to arrest in G1. DNA damage results in phosphorylation of both p53 and Mdm2 on the domains where they normally interact. Therefore, a p53-Mdm2 complex cannot form and p53 degradation is not promoted. P53 accumulates. Functioning as a transcription factor, p53 turns on transcription of DNA repair genes and of WAF1, which encodes a protein called p21. The p21 protein binds to the G1 to S checkpoint Cdk4-cyclin D complexes and inhibits their activity. As a result, pRB in the pRB complex does not become phosphorylated, thereby keeping e2F inhibited. Entry into S phase is blocked and the cell arrests in G1.
The p21 protein can also bind to other checkpoint Cdk-cyclin complexes and inhibit their activity, thereby blocking the cell cycle at any stage. The example here focuses on the retinoblastoma protein and the G1 to S checkpoint.

a. Is the TP53 gene considered a proto-oncogene or a tumor suppressor gene? Explain your answer.

b. Why is the WAF1 gene considered a tumor suppressor gene? Explain your answer

c. Why are mutations in the WAF1 gene and other tumor suppressor genes considered recessive mutations?

d. How might a point mutation create an inactive form of p53?