AS Biology 9700: RAS Oncogene and p53 Mutations in Uncontrolled Mitosis

Two genes involved in the normal control of the cell cycle are RAS, a proto-oncogene whose product normally helps to relay a signal that stimulates a cell to divide, and p53, a tumour-suppressor gene whose product normally halts the cell cycle at a checkpoint if DNA damage is detected. Mutations affecting either gene are commonly found in tumour cells.

(a) Explain, in terms of the normal function of RAS, how a mutation converting this proto-oncogene into an oncogene can promote uncontrolled mitosis. [3]

(b) Explain, in terms of the normal function of p53, how a mutation that inactivates this tumour-suppressor gene can allow a cell to continue dividing by mitosis when it should not. [3]

(c) State one similarity between the overall effect that a RAS oncogene mutation and a p53 mutation each have on the control of the cell cycle. [1]

Part (a): RAS and uncontrolled mitosis

The normal product of the RAS proto-oncogene is part of a cell signalling pathway that relays a “divide” signal to the cell, helping to stimulate progression through the cell cycle when this is appropriate, for example when a growth signal has been received from outside the cell. This signalling is normally switched on and off as needed. A mutation that converts RAS into an oncogene typically alters its product so that it becomes permanently active, or far more active than normal, regardless of whether the correct external signal is present. As a result, the cell continuously receives a strong internal signal to divide, driving it to repeatedly enter and progress through the cell cycle and undergo mitosis even when division is not appropriate, contributing to the uncontrolled proliferation seen in a tumour.

Part (b): p53 and uncontrolled mitosis

The normal product of the p53 tumour-suppressor gene monitors the cell for DNA damage and acts at a cell cycle checkpoint: if damage is detected, p53 halts the cell cycle, giving the cell time to repair the damage, or, if the damage is too severe to repair, triggers the destruction of the cell. This prevents cells with damaged or mutated DNA from continuing to divide. A mutation that inactivates p53 destroys this checkpoint function, so a cell with damaged DNA is no longer halted, repaired, or removed. Instead, that cell is free to continue through the cell cycle and undergo mitosis, and because its DNA damage is never corrected, this abnormal genetic state (and any further mutations that build up) is passed on to its daughter cells, allowing uncontrolled division to continue.

Part (c): A shared outcome

Although the RAS and p53 mutations act through opposite mechanisms (the RAS oncogene mutation provides an excessive stimulus to divide, whereas the p53 mutation removes a restraint that would normally stop division) both ultimately have the same overall effect on the control of the cell cycle: they allow a cell to keep dividing by mitosis in circumstances where a normal cell would not, contributing to uncontrolled cell division and the growth of a tumour.

Final answers

(a) A mutated RAS oncogene produces a permanently (or excessively) active “divide” signal, continuously stimulating the cell to enter the cell cycle and undergo mitosis.
(b) A mutated, inactive p53 can no longer halt the cell cycle in response to DNA damage, so damaged cells are not stopped, repaired or destroyed, and continue dividing by mitosis.
(c) Both mutations result in the cell dividing by mitosis when it should not, despite reaching this outcome by opposite mechanisms (gain of a stimulus versus loss of a restraint).