WK1: Resisting cell death

What is the third hallmark of cancer?

Resisting Cell Death (also called Evading Apoptosis) – cancer cells must avoid programmed cell death to survive and proliferate.

What is the function of normal p53 protein?

Normal p53 destroys cells that have irreparable damage to their DNA – preventing cancer development.

What happens when p53 is mutated?

Abnormal p53 fails to stop cell division. Damaged cells continue to divide and cancer develops.

In what percentage of cancers is p53 mutated?

Greater than 50% of all human cancers have mutations in the p53 gene.

List at least 4 diverse functions of p53.

1) Cell cycle arrest (via p21). 2) DNA repair activation. 3) Apoptosis induction (via Bax Puma Noxa). 4) Senescence induction. 5) Differentiation promotion. 6) Angiogenesis inhibition (via thrombospondin-1).

What two major anti-cancer functions does p53 have from the previous two hallmarks?

From Evading Growth Suppressors: p53 arrests the cell cycle for DNA repair. From Resisting Cell Death: p53 induces apoptosis when damage is irreparable.

Why is p53 called the "guardian of the genome"?

Because it protects genomic integrity by detecting DNA damage pausing the cell cycle to allow repair and triggering apoptosis if damage is irreparable – preventing mutations from being passed on.

What are the 4 main causes of genomic instability?

1) Loss or mutation of p53 (DNA damage sensor). 2) Breakdown in DNA repair mechanisms (e.g. mismatch repair base excision repair). 3) Mutagenic agents (chemicals radiation). 4) Viruses. Often a combination of these factors.

How do cancer cells benefit from increased mutation rates?

Cancer cells take advantage of increased rates of mutations to accumulate the mutations needed to foster tumorigenesis and acquire hallmark capabilities.

Complete this sentence: "Normal p53 protein destroys cells that have ___________ damage to their DNA. Abnormal p53 fails to stop ___________ so damaged cells divide and cancer develops."

Normal p53 destroys cells with IRREPARABLE damage. Abnormal p53 fails to stop CELL DIVISION so damaged cells divide.

What is the connection between p53 loss and genomic instability?

p53 normally detects DNA damage and either arrests the cell cycle for repair or triggers apoptosis. When p53 is lost/mutated damaged cells continue to divide passing on mutations and causing genomic instability.

What happens to DNA repair when p53 is mutated?

p53 normally activates DNA repair mechanisms. When p53 is mutated DNA repair is compromised and damaged DNA is not fixed before the cell divides.

What is the connection between p53 and angiogenesis?

p53 upregulates thrombospondin-1 (TSP-1) which is an endogenous inhibitor of angiogenesis. When p53 is lost TSP-1 levels drop removing this brake on blood vessel growth.

How does p53 induce apoptosis?

p53 upregulates pro-apoptotic proteins including Bax Puma and Noxa. These proteins trigger mitochondrial cytochrome c release leading to caspase activation and apoptotic cell death.

What is the difference between how p53 and Rb control the cell cycle?

Rb controls the G1→S checkpoint by binding E2F. p53 responds to DNA damage by inducing p21 which inhibits CDKs leading to Rb hypophosphorylation and cell cycle arrest. Both converge on Rb but respond to different signals.

Why is p53 loss more dangerous than loss of a single cell cycle regulator?

p53 loss removes multiple barriers simultaneously: cell cycle arrest DNA repair apoptosis AND angiogenesis inhibition. Loss of a single cell cycle regulator like Rb can be compensated but p53 loss is catastrophic for genome stability.

What is the relationship between p53 mutation and the "Evading Growth Suppressors" hallmark?

p53 is a tumour suppressor gene. When p53 is mutated cancer cells successfully EVADE growth suppressors because the cell cycle arrest function of p53 is lost.

What is the relationship between p53 mutation and the "Resisting Cell Death" hallmark?

p53 triggers apoptosis in response to DNA damage. When p53 is mutated cancer cells successfully RESIST cell death because the apoptosis function of p53 is lost.

How does p53 mutation contribute to the "Sustaining Proliferative Signalling" hallmark?

p53 mutation allows damaged cells to continue dividing without p21-mediated cell cycle arrest. This indirectly contributes to sustained proliferation by removing a critical brake.

Which viruses target p53 and how?

HPV (human papillomavirus) produces the E6 protein which binds and degrades p53. This disables both p53-mediated cell cycle arrest and apoptosis contributing to cervical cancer.

Why do cancer cells with p53 mutations have a selective advantage?

p53-mutant cells survive DNA damage that would normally trigger apoptosis in normal cells. They also continue to divide with mutations some of which may confer additional growth advantages.

What does "irreparable DNA damage" mean in the context of p53 function?

DNA damage that cannot be successfully repaired by cellular repair mechanisms. p53 detects this and triggers apoptosis rather than allowing the damaged cell to divide.

Complete the sentence from slide 10: "Cancer cells take advantage of increased rates of mutations in order to ___________"

accumulate the mutations needed to foster tumorigenesis

Why is p53 considered relevant to multiple hallmarks of cancer?

p53 regulates cell cycle arrest (Evading Growth Suppressors) apoptosis (Resisting Cell Death) and angiogenesis (Inducing Angiogenesis). Its loss enables at least three distinct hallmark capabilities.