Which of the following is the most likely explanation for this observation?

Analysis of a tumor cell line indicates that there is a dramatically increased level in the activity of the transcription factor E2F. Which of the following is the most likely explanation for this observation?

(A) an increase in the expression of pRB resulting in increased binding of pRB to E2F
(B) hypophosphorylation of pRB so that it can no longer interact with E2F
© loss of expression of pRB which normally activates E2F
(D) mutation in pRB that prevents its phosphorylation so that it cannot interact with the gene to which it normally binds and coactivates with E2F
(E) mutation in the domain of pRB to which E2F binds, the consequences of which lead to constitutive E2F activity

Explanation

(E) Members of the E2F family of transcription factors play critical roles in regulating cell-cycle transit through the G1-S restriction point. The activity of E2F is regulated by interaction with the protein product of the retinoblastoma susceptibility tumor suppressor gene, pRB. Interaction of pRB and E2F occurs when pRB is in a hypophosphorylated state (Figure 3-8). Members of the cyclin-dependent kinase family of cell-cycle regulating kinases target pRB for phosphorylation. When phosphorylated, pRB dissociates from E2F allowing E2F to enter the nucleus and transcriptionally activate genes involved in DNAsynthesis, as well as activate its own transcription. Transcription of both cyclin E and CDK2 are activated by E2F. These two proteins form a complex that promotes progression through S-phase of the cell cycle and also act to keep E2F active by adding to the phosphorylation state of pRB (Figure 3-8). Thus, any defect in the ability of pRB to bind to E2F will lead to constitutive activation of DNA synthesis leading to unrestrained proliferation. None of the other options (choices A–D) represent viable phenomena to account for the observed increase in E2F activity.