Lecture 6: Tumor Suppressors Flashcards
Tumor Suppressor Gene
Gene that encodes a protein that regulates cell division, keeping it in check. Can be inactivated by mutation, methylation, or post-translational modification.
Cancer susceptibility gene
A gene that when changed/mutated gives an individual an increased risk of developing cancer.
2 main functions of tumor suppressors
- Gatekeepers: Check progression through cell cycle and cell division
- Caretakers: Maintenance of cellular genome
5 functional types of tumor suppressor GENES
- Cell cycle progression
- Receptors or signal transducers
- Checkpoint-control proteins
- Induction of apoptosis
- Repair of DNA
7 biological functions of tumor suppressor PROTEINS
- Inhibition of mitogenic signaling pathways
- Inhibition of cell cycle progression
- Inhibition of “Pro-growth” programs of metabolism and angiogenesis
- Inhibition of invasion and metastasis
- Maintain chromosomal stability
- DNA repair factors
- Induction of apoptosis
Hereditary cancer syndrome
Genetic predisposition to certain types of cancer, often with onset at an early age.
Predisposition
A type of inherited disorder in which there is a higher than normal risk of certain types of cancer.
Gene who causes Cowden syndrome
PTEN
Cowden syndrome
Rare inherited disorder marked by presence of many benign, non-cancerous growths called hamartomas and increased risk for developing cancerous tumors.
Familial Adenomatous Polyposis
Lining of the colon with numerous small polyps
Li-Fraumeni Syndrome
Hereditary disorder that increases the risk you and your family will develop cancer
Neurofibromatosis Type 1
Genetic condition that causes tumors to grow along the nerves. Tumors are usually non-cancerous but can become cancerous.
Gene associated with Familial adenomatous polyposis
APC
Cowden Syndrome
PTEN
Li-Fraumeni Syndrome
P53
Indicators for potential hereditary risk
-Cancer occurring at young age
-Individuals from families with known mutation associated with cancer risk
-Family history that indicates risk
-1st or 2nd degree relative with any cancer diagnosis under 45 of sarcoma at any age
-Any pattern of cancer association
-Presence of premalignant conditions
Retinoblastoma
Condition that causes variety of mechanisms like loss of function mutations and inhibition of RB by binding of viral oncoprotein to inhibit RB anti-proliferative effects in cancer.
RBgene
Encodes RB protein that inhibits E2F transcription factors. Transcription factors regulate genes essential for cells to pass from G1 to the S phase of cell cycle.
Origin of pediatric retinoblastomas
Arises from precursor of cone cells
Leukocoria
Abnormal reflection of a “White Pupil” from greek word leukos for white and kore for pupil. Refers to reflection of white light in pupil
Two hit hypothesis
Since most loss-of-function mutations are recessive, both of the tumor suppressor gene cells must be mutated
Survival rate of retinoblastomas
95%
Two-hit hypothesis in sporadic retinoblastoma
Both normal RB alleles undergo somatic mutation in the same cell. Probability is low.
Two-Hit hypothesis in inherited retinobladtomas
Children inherit one RB allele and retinoblastoma develops when the normal RB undergoes a spontaneous somatic mutation known as “The second hit”
Two-hit theory in BRCA1 and BRCA2
When one of the 2 active copies of these genes becomes inactive a persons remaining copy will become inactivated causing uncontrolled cell growth
Why are mutant proto-oncogenes usually not transmitted to germ line
These mutant cells likely disturb normal cell behavior and disrupt normal tissue development, therefore, embryos rarely develop to term. This causes mutant alleles to disappear from germ-line
Why are mutant tumor suppressor genes transmitted through germ-line
Since these alleles often are recessive their presence is usually absent and therefore compatible in embryo development. Cancerous phenotypes become apparent in small number of cells after large delay
9 Hallmarks of aging
-Genomic instability
-Telomere attrition
-Epigenetic alterations
-Loss of proteostasis
-Disregulated nutrient-sensing
-mitochondrial dysfunction
-Cellular senescence
-Stem cell exhaustion
-Altered intercellular communication
Cellular senescence
Prevents the proliferation of damaged cells to prevent cancer and promote tissue homeostasis.
P53 function in aging process
Decline of function shows possible mechanism for increased tumor incidence
P53 Loss
Critical factor in promoting genomic
BRCA1 Loss of function
Results from reduced protein expression or incorrect subcellular localization. and works in DNA repair, gene modulation, and cell cycle arrest
5 mechanisms of PTEN malignancy
-Mutations
-Methylation
-RNA/Transcriptional
-miRNA
-Post-translational modifications
Therapeutic approach to compensate for PTEN loss of function
Rapamycin activating mTOR inhibitors in combination treatment to overcome cancer resistance to treatment
Promoter methylation
Important mechanism for inactivating tumor suppressor genes
Loss of heterozygosity
Loss of one parents contribution to cell known to be involved in somatic loss of wild-type alleles in many inherited cancer syndromes
