Cancer
Cancer is the result of somatic mutations that affect cell growth and division
Once cell gains immortality, tumor may stay in one place (benign) or metastisize (malignant). Metastasis requires additional mutations to occur that result in loss of adhesive properties (such that cell will break off of the tumor) and the ability to penetrate other tissues.
Mutations may be spontaneous (rare) or due to mutagens (carcinogens)
2 genes affect cancer: oncogenes and tumor-suppressor genes (anti-oncogenes)
Oncogenes
Normal form is the proto-oncogene; have two copies because the cell is diploid
May mutate to form an oncogene
If only one copy of the proto-oncogene is mutated to an oncogene, has a negative effect
Have retroviruses that carry oncogenes and can pass them on to new host
Detect oncogenes in the lab by transforming cells in tissue culture; if take up an oncogene the cells now lack contact inhibition and will form tumors, not monolayer
Mutation to form an oncogene may be:
1) Mutation in coding sequence of proto-oncogene that results in the production of a hyperactive protein
2) Duplication of a proto-oncogene such that more protein is produced
3) Translocation of a proto-oncogene downstream of a strong, constitutive promoter
Normal proto-oncogenes are either:
1) Growth factors that bring the message to divide to the cell
2) Cell surface receptors that recognize the growth factors and receive the signal
3) Signal transduction proteins that pass the signal on by phosphorylating certain proteins involved in cell division and making them active (e.g. protein kinase will phosphorylate proteins)
4) Transcription factors that respond to the signal by turning up the transcription of genes involved in cell division
Example of an oncogene: ras oncogene
RAS protein involved in signal transduction. Normal RAS protein responds to an external division signal by binding GTP to become active and pass the signal on. Once the signal is passed on, the GTP divides to GDP and RAS is inactive
Single base substitution in the ras gene that results in a single a.a. change will result in the production of a mutant RAS protein that permanently binds GTP (can't split the GTP) so that the protein is always active so is always telling the cell to divide, even in the absence of any external hormonal division signal
Example of an oncogene: myc oncogene
MYC protein is a transcription factor that switches on the expression of several genes involved in cell division
Can get cancerous effects from MYC in one of two ways: may duplicate myc gene 50- 100 times and overproduce the protein or the myc gene may be involved in a translocation event such that it is now constitutively expressed
Tumor-suppressor genes (anti-oncogenes)
Encode proteins that inhibit cell division either by stopping transmission of an external signal or by allowing only a pre-set number of cell divisions to occur
Two copies because cell is diploid
If mutate only 1 copy won't get an effect because normal protein is still made by the unmutated gene. Must mutate both copies of the gene to initiate cancerous growth.
May have two somatic mutations occur in same cell so that both copies of the gene are now mutant (rare) or may inherit a mutated gene and only need to mutate the other copy to get the negative effect (inherit a predisposition to cancer)
Cell cycle:
1) G1 phase: cell growth
2) S phase: chromosomal replication
3) G2 phase: cell grows and prepares to divide
4) M phase: cell and nuclear division
Cyclin proteins allow transition from one phase to another
Cyclins bind CDK (cyclin dependent kinases) which are then activated and phosphorylate other proteins
Example of a tumor-suppressor gene: p53 tumor-suppressor gene
Acts to stop cell division in emergencies such as DNA damage by activating either the p21 or p16 proteins which freezes the cell in the cell cycle by blocking the action of the cyclins. p21 blocks the action of all cyclins while p16 only blocks the action of one of them (cyclin E - transition from G1 to S phase).
p53 is involved in over half of all human cancers because if only one of the copies of the gene is mutated, the protein can't activate p21 or p16 because the protein works as a tetramer, and if any subunit of the 4 is bad (a mixed tetramer), the tetramer can't work. If one copy of the p53 gene is mutated, there's only a 1/16 chance of forming a normal tetramer.
Inherited Susceptibility to Cancer
1) Inherit one mutant copy of a tumor-suppressor gene. i.e. Inherit mutant BRCA1 gene and women have increased chance of getting breast and ovarian cancer. 0.5% of women have this mutation.
2) Inherit mutant mutator gene such as DNA polymerase gene or genes encoding proteins involved in mismatch repair
3) Genetic differences between races or populations. i.e. Light-skinned people get skin cancer more often than dark-skinned people.
Retroviruses
RSV - Rous Sarcoma Virus - carries copy of chicken oncogene
15% of human cancers due to viruses
i.e. DNA tumor viruses. DNA integrates, makes protein that binds p53
Gene Therapy for Cancer
Direct attack
Tumor Necrosis Factor (TNF) normally produced by white blood cells called tumor-infiltrating lymphocytes. Culture white blood cells from patient, transform with TNF gene cloned behind a powerful promoter and inject back into patient.
Indirect attack
Insert HLA (human leukocyte antigen) gene into cancer cells only; immune system recognizes as foreign and destroys. Can get gene into cancer cells by lipofection - injection of liposomes carrying DNA (or protein)
Can only avoid cancer by dying of something else first
Aging
Chromosome can only divide about 50 times because of shrinking telomere
Telomerase can help restore telomere but function declines with age
Cancer cells can undergo a greater number of cell divisions than permitted for normal cells (become immortal) partly due to a reactivation of telomerase gene
Telomerase carries complementary RNA for recognizing the telomere. Can use an antisense RNA to block the complementary RNA and stop telomerase function. This approach does inhibit cancer cells in culture.
Caenorhabditis elegans (nematode) has normal 25-day life span. Will live to 50 days if has a mutant daf-2 gene
Apoptosis - pre-programmed cell death
Animal cells stay alive because of signal received from protein made by ced-9 gene (in C. elegans). If ced-9 defective, cells commit premature suicide and organism dies. If ced-9 is mutated to another form, cells that should have sacrificed themselves stay alive.
ced-9 gives orders to ced-3 and ced-4 (the molecular hit men).
In humans, this involves a suite of genes rather than just one.
bcl-2 oncogene may function like ced-9. If it's hyperactive, cells don't die and cancer may result. If it's nonfunctional, premature cell death occurs. Engineered mice with 2 mutant copies of bcl-2 are normal at birth but usually die within a week or two from apoptosis of the thymus and spleen; those that survive turn gray and then soon die.
Another factor other than telomere length that results in aging is the loss of energy-producing genes in the mitochondrial DNA. Mutations accumulate and many of these mutations occur in the genes involved in energy production and even large deletions occur that wipe out most of these genes. So in older people, many more of their mitochondria simply don't put out the energy of a younger person so they have less efficient heart cells, brain cells, etc. Some people age faster presumably because they've inherited some mitochondria that are already mutated. Since you inherit your mitochondria only from your mother, if your maternal line has a history of living long, you may also live long.
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Last updated: 12-April-06 / laa