cancer cells: excessive birth rate
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122 Terms
What are the two major classes of cancer genes?
Oncogenes and tumour suppressor genes.
What is an oncogene?
A gene that promotes uncontrolled cell proliferation when activated or overexpressed.
What is a proto-oncogene?
A normal gene that promotes cell growth and division under regulated conditions.
How does a proto-oncogene become an oncogene?
Through activating mutations, amplification, or chromosomal translocation.
What is the normal function of proto-oncogenes?
To stimulate cell growth, proliferation, and survival when appropriate.
What is a tumour suppressor gene (TSG)?
A gene that inhibits proliferation, repairs DNA damage, or promotes apoptosis.
How do tumour suppressor genes prevent cancer?
They restrain cell cycle progression and maintain genomic integrity.
What is the accelerator pedal analogy for oncogenes?
Oncogenes act like a stuck accelerator that continuously drives proliferation.
What is the brake pedal analogy for tumour suppressor genes?
Tumour suppressor genes act like brakes that prevent uncontrolled growth.
What combination of genetic changes commonly causes cancer?
Oncogene activation and tumour suppressor gene inactivation.
What is a gain-of-function mutation?
A mutation that increases or constitutively activates protein function.
Which type of mutation commonly activates oncogenes?
Gain-of-function mutations.
What is a loss-of-function mutation?
A mutation that reduces or abolishes protein function.
Which type of mutation commonly affects tumour suppressor genes?
Loss-of-function mutations.
Why is one mutated oncogene allele usually sufficient for cancer promotion?
Oncogene mutations are dominant at the cellular level.
Why are two tumour suppressor gene hits usually required?
The remaining normal allele can often maintain function.
What is Knudson's two-hit hypothesis?
Both copies of a tumour suppressor gene must be inactivated for loss of function.
What is the first hit in Knudson's model?
Inherited or acquired mutation affecting one allele.
What is the second hit in Knudson's model?
Loss, mutation, or silencing of the remaining normal allele.
How can gene amplification activate an oncogene?
Extra gene copies increase protein production.
What are double minute chromosomes?
Small extrachromosomal DNA fragments containing amplified oncogenes.
How does chromosomal translocation activate oncogenes?
It places genes under control of highly active promoters or enhancers.
How can promoter hypermethylation contribute to cancer?
It silences tumour suppressor gene expression.
How can gene deletion contribute to cancer?
It removes tumour suppressor genes.
What is EGFR?
A receptor tyrosine kinase that promotes cell proliferation after growth factor binding.
What is the normal ligand for EGFR?
Epidermal growth factor (EGF) or transforming growth factor alpha (TGF-α).
How is EGFR normally activated?
Ligand binding induces receptor dimerisation and signalling.
How does EGFR amplification promote cancer?
Excess receptors produce excessive growth signalling.
How does an activating EGFR mutation promote cancer?
The receptor becomes active without ligand binding.
What is constitutive activation?
Continuous protein activity independent of normal regulatory signals.
Why are constitutively active receptors oncogenic?
They continuously stimulate proliferation.
What is HER2/ERBB2?
A growth factor receptor oncogene frequently amplified in cancer.
How does HER2 amplification contribute to tumour growth?
It increases growth signalling pathways.
What is Ras?
A signalling protein that transmits growth factor signals from receptors to the nucleus.
What is the active form of Ras?
Ras bound to GTP.
What is the inactive form of Ras?
Ras bound to GDP.
How is Ras normally switched off?
Intrinsic GTPase activity converts GTP to GDP.
How do KRAS mutations promote cancer?
They reduce GTPase activity, locking Ras in the active state.
What is the consequence of constitutively active Ras?
Persistent growth and proliferation signalling.
What is BRAF?
A downstream kinase in the Ras signalling pathway.
How do BRAF mutations contribute to cancer?
They cause continuous activation of proliferation pathways.
What is PIK3CA?
An oncogene involved in cell growth and survival signalling.
How do PIK3CA mutations promote cancer?
They activate survival and proliferative pathways.
What is MYC?
A transcription factor that promotes expression of genes required for growth and proliferation.
How does MYC amplification contribute to cancer?
It increases transcription of proliferation-associated genes.
What is CCND1?
The gene encoding cyclin D1.
How does cyclin D1 promote cell cycle progression?
It activates CDK4 and CDK6.
How does CCND1 amplification contribute to cancer?
Excess cyclin D1 causes excessive cell cycle progression.
What is CDK4?
A cyclin-dependent kinase that promotes progression through G1.
What activates CDK4?
Binding of cyclin D1.
What is the restriction point (R point)?
The checkpoint in late G1 after which a cell is committed to division.
Why is the restriction point important?
It prevents inappropriate cell cycle entry.
What is pRb?
The retinoblastoma protein that regulates the G1 restriction point.
What is the normal function of pRb?
To suppress transcription factors required for S phase entry.
Which transcription factor is inhibited by pRb?
E2F.
How does active pRb inhibit proliferation?
It binds E2F and prevents transcription of S-phase genes.
When is pRb active?
When weakly phosphorylated.
When is pRb inactive?
When highly phosphorylated.
How does cyclin D-CDK4 affect pRb?
It phosphorylates and inactivates pRb.
What happens when pRb is inactivated?
E2F is released and S-phase genes are transcribed.
How does RB1 loss promote cancer?
Cells bypass the restriction point and enter S phase uncontrollably.
How can RB1 be inactivated?
Mutation, deletion, or promoter methylation.
Is RB1 only important in retinoblastoma?
No, RB1 is altered in many human cancers.
Approximately what proportion of cancers show RB1 inactivation?
About 25%.
What is p16INK4a?
A CDK inhibitor encoded by CDKN2A.
What is the function of p16INK4a?
It inhibits CDK4 and CDK6 activity.
How does loss of p16INK4a promote cancer?
CDK4 activity increases, causing excessive pRb phosphorylation.
What is CDKN2A?
A tumour suppressor gene encoding p16INK4a.
What is CDKN2B?
A tumour suppressor gene encoding p15, another CDK inhibitor.
How does CDKN2A deletion contribute to tumour formation?
Loss of CDK inhibition allows uncontrolled G1 progression.
What is p53?
A tumour suppressor protein that responds to cellular stress and DNA damage.
Why is p53 called the guardian of the genome?
It prevents propagation of genetically damaged cells.
How is p53 activated?
By DNA damage, oncogenic stress, or cellular injury.
What is one major function of p53?
Cell cycle arrest following DNA damage.
How does p53 induce cell cycle arrest?
By stimulating p21 expression.
What is p21CIP?
A cyclin-dependent kinase inhibitor induced by p53.
How does p21 inhibit proliferation?
It blocks cyclin-CDK complexes.
What happens when p53 is mutated?
Damaged cells continue through the cell cycle.
How does p53 loss contribute to genomic instability?
DNA damage accumulates without repair.
Which cancer-associated gene is most frequently mutated?
TP53.
Approximately what percentage of cancers contain TP53 mutations?
About 28.5%.
What is apoptosis?
Programmed cell death.
How can p53 induce apoptosis?
By activating pro-apoptotic genes when damage is irreparable.
How does loss of p53 promote cancer cell survival?
Abnormal cells avoid apoptosis.
What is genomic instability?
An increased tendency to accumulate genetic alterations.
How does cell cycle checkpoint failure promote cancer?
Mutated DNA is passed to daughter cells.
What occurs during G1 phase?
The cell assesses growth signals and environmental conditions.
What occurs during S phase?
DNA replication.
What occurs during G2 phase?
Preparation for mitosis and DNA quality control.
What occurs during M phase?
Mitosis and cell division.
What are cyclins?
Proteins that regulate progression through the cell cycle.
What are cyclin-dependent kinases (CDKs)?
Kinases activated by cyclins that drive cell cycle transitions.
Which cyclin-CDK complex controls early G1 progression?
Cyclin D-CDK4/6.
Which cyclin-CDK complex drives G1/S transition?
Cyclin E-CDK2.
Why are cyclins called cell cycle activators?
They promote progression through checkpoints.
What are CDK inhibitors?
Proteins that block cyclin-CDK activity.
Why are CDK inhibitors tumour suppressors?
They restrain inappropriate proliferation.
What is growth factor independence?
The ability to proliferate without external growth signals.
Why is growth factor independence advantageous to cancer cells?
They no longer depend on surrounding tissues for stimulation.
What is autocrine signalling?
A cell produces growth factors that stimulate itself.