The triad of Parkinson's is:
Bradykinesia, Rigidity and Tremor.
Other signs:
Mask-like face (apathetic), shuffling gait, depression, stooped posture, dystonia, anosmia, postural instability, generalised fatigue, micrographia, sleep disturbance and executive dysfunction.
Parkinson's can be caused genetically by alpha-synuclein gene mutation. Lewy bodies and increased ubiquitinated proteins are involved- oxidative stress can be the cause of these proteins as they create tissue damage. L-DOPA leads to the production of O2 radicals which damage the tissues.
L-Dopa is the usual treatment for dopamine deficiency as it crosses the blood brain barrier. Carbidopa and Entacapone both act in the periphery to reduce the metabolism peripherally- these drugs therefore keep the L-Dopa in a state that can cross the blood-brain barrier. Dopamine itself cannot cross the barrier.
Selegiline is a MAO-beta inhibitor which means the dopamine will stay in the synapse for longer.
Notes From Medical School
Cram notes: Cerebellar function
Vertigo
Ataxia
Nystagmus
Intention tremor
Slurred speech
Hypotonic reflexes
Exagerrated broad based gait
Dysdiadochokinesia
Ataxia
Nystagmus
Intention tremor
Slurred speech
Hypotonic reflexes
Exagerrated broad based gait
Dysdiadochokinesia
Cram notes: Intracellular signalling
SPECIFICITY
TRANSDUCTION
AMPLICATION
REPLICATION
Ligands can be any small molecule; peptides, amino acids, steroids, prostaglandins.
The response of the cell might be altered motility, altered activation, survival, division, angiogenesis or death.
Mitogenesis
Apoptosis
Invasion
Metastasis
Mitogenesis is the EGF, PDGF or VEGF which cause growth and proliferation. The receptors have tyrosine kinase activity- more activation leads to a cascade of growth signals. This is carcinogenic. Peptides and lipids can act of G-PCRs. Cytokines can bind to adaptor proteins and lipid protein kinases.
PDGF is to do with platelets- it promotes the proliferation of connective tissue.
EGF is from the submaxillary glands and it is particularly vital in the proliferation of epithelial cells.
TGFA is related to EGF.
TGFB is from activated T-helper cells and is involved in the anti-inflammatory response.
VEGF is involved in angiogenesis.
Kinases catalyses the removal of phosphate from ATP and its placed onto another molecule. Phosphorylation might turn a protein on or off.
Hallmarks of cancer:
Evades apoptosis
Self sufficient in growth signals
Limitless replicative potential
Invade and Metastasises
Insensitive to anti-growth signals
Sustains angiogenesis
Mitogenic signalling:
SHC + Grb2 + Sos --> phosphorylate RAS-GDP to RAS-GTP --> Raf --> Mek --> Mapk --> Erk activates gene expression
Survival factors prevent the normal apoptosis of cells. Survival can be triggered by cytokines and growth factors. Integrins also provide anti-apoptotic signals. IGF plays a role in telling the cell not to apoptose. Upregulation causes too much signal and there is growth.
EGF --> PI3K --> PIP3 is usually converted back to PIP2 by PTEN which causes apoptosis by preventing signalling. PIP3 --> PDK --> ATK --> PKV --> INHIBITION OF APOPTOSIS
There is a lot of redundancy in cell signalling as many pathways can cause the same thing. The cancer generates the ability to generate its own survival signals by constitutively active receptors. This can occur by protein mutation or removing an inhibitory signal, or adding a complementary pathway; or just amplifying the signal.
Intracellular signals usually use protein interactions or lipid alterations. Second messengers are usually rapidly generated, diffusible and removed. It is a quick process and fulfills the amplification requirements. Conformational changes usually occur that cause the 2nd messenger. There is increased localisation or concentration of something downstream.
Chemotherapy acts to stop the cell division from occurring. However, this causes side effects because it acts on all rapidly dividing cells.
HER2 in breast cancer signals through the RAS pathway. This leads to mitogenesis and survival. This is a normal signalling pathway but in HER2 positive breast cancer there are a lot more of these receptors available so an increased signal. Women who have this have a shorter survival overall due to this mechanism. Herceptin is a drug that has been used to target these receptors and reduce this problem.
Cram notes: viruses in human cancer
Infectious agents are responsible for 20% of cancers worldwide. Vaccinations and therapies should work on cancers caused by such agents. In total infectious cancers worldwide there are the following indicated:
Human papillomavirus - cervical cancer
Hepatitis B and C - liver cancer
HIV and Kaposi's sarcoma
Oncogenesis is the accumulation of genetic changes that alter proteins that control cell growth and division. Oncogenic virsuses can affect these changes. Retroviruses insert DNA into our DNA which can alter human DNA to upregulate these things.
Human viruses:
HPV - cervical cancer
Herpes - Kaposi's sarcoma and Epstein-Barr Virus (after immunosuppression)
HBV and HCV - liver cancer
Most important ones:
Immune control is vital in cancer development, as usually the immune system controls elimination, equilibrium and finally evasion.
Koch's postulates:
- regular association
- virus can be taken from host and grown in culture
- reintroduced virus causes disease
- reintroduced virus can be extracted and grown in culture
This does not occur in all viruses that are involved in human cancer.
Obviously introducing vaccines has been shown to reduce the rate of cancer.
KSHV is an AIDs defining illness. There are different types of KS and it was first seen in elderly Mediterranean men and then it became noticeable in a number of young homosexual men. This was associated with HIV. It can also be caused in an iatrogenic way or endemically.
In HIV infection there is a 200,000 times higher incidence of KSHV than in the general population. There is a proved connection between KS and KSHV. In the spindle cells of KS there is Latent nuclear antigen (LANA). KS causes tumour products transcriptionally. In KSHV there are phenotypic changes from cobblestone to spindle cells.
Koch's postulates have been updated as they don't work exactly in relation to viruses associated with cancer. The viruses are obviously related and the tumours show copies of the KSHV, however, it can't be isolated and reintroduced- ethically this is not viable! In macaque monkeys this has been shown to increase the chance of tumour.
Zur Hausen updated the criteria:
-regular presence and persistance in biopsies
-growth promotion of upregulated genes
-malignant phenotype dependent on expression of the genes
-major risk factor for the development of tumour
Eukaryotic cell cycle is a very ordered process which means all the right factors need to come together to downregulate inhibition and increase the proliferation. The signals are produced in the cell and it regulates itself. The processes are M, G1, S and G2. Cytokines regulate the whole process, which cyclins. CDKs are involved. Usually the inhibitors of the cyclins and cytokines prevent proliferation.
HPV affects the non-differentiating keratinocytes to replicate in an unregulated manner. In the upregulation, the host usually acts to prevent proliferation by trying to apoptose cells usually but HPV suppressing the RB gene and phosphorylating this protein and suppressing p53. HPV E6 binds to p53 causes lack of transcription of cell cycle inhibitors. We can vaccinate against this by giving empty capsids, meaning you get the immune response to the virus stopping you from getting it.
Newcastle disease from chickens can cause an 'immunity' to stomach cancer!
Retroviruses cause the responses. However, there can be latency as the virus needs to insert near the gene it wants to activate to cause the change in the cell cycle. For example, if the virus is near c-myc gene this upregulates the gene. It is hard to attribute the cause to a virus.
Tumour associated viruses show us a lot about which genes are essential in cancer.
Novel therapeutic approaches involve vaccines.
Human papillomavirus - cervical cancer
Hepatitis B and C - liver cancer
HIV and Kaposi's sarcoma
Oncogenesis is the accumulation of genetic changes that alter proteins that control cell growth and division. Oncogenic virsuses can affect these changes. Retroviruses insert DNA into our DNA which can alter human DNA to upregulate these things.
Human viruses:
HPV - cervical cancer
Herpes - Kaposi's sarcoma and Epstein-Barr Virus (after immunosuppression)
HBV and HCV - liver cancer
Most important ones:
Hepatitis C
Human T-cell leukaemia virus type 1
Human Papillomavirus
Epstein-Barr virus
Hepatitis B
Immune control is vital in cancer development, as usually the immune system controls elimination, equilibrium and finally evasion.
Koch's postulates:
- regular association
- virus can be taken from host and grown in culture
- reintroduced virus causes disease
- reintroduced virus can be extracted and grown in culture
This does not occur in all viruses that are involved in human cancer.
Obviously introducing vaccines has been shown to reduce the rate of cancer.
KSHV is an AIDs defining illness. There are different types of KS and it was first seen in elderly Mediterranean men and then it became noticeable in a number of young homosexual men. This was associated with HIV. It can also be caused in an iatrogenic way or endemically.
In HIV infection there is a 200,000 times higher incidence of KSHV than in the general population. There is a proved connection between KS and KSHV. In the spindle cells of KS there is Latent nuclear antigen (LANA). KS causes tumour products transcriptionally. In KSHV there are phenotypic changes from cobblestone to spindle cells.
Koch's postulates have been updated as they don't work exactly in relation to viruses associated with cancer. The viruses are obviously related and the tumours show copies of the KSHV, however, it can't be isolated and reintroduced- ethically this is not viable! In macaque monkeys this has been shown to increase the chance of tumour.
Zur Hausen updated the criteria:
-regular presence and persistance in biopsies
-growth promotion of upregulated genes
-malignant phenotype dependent on expression of the genes
-major risk factor for the development of tumour
Eukaryotic cell cycle is a very ordered process which means all the right factors need to come together to downregulate inhibition and increase the proliferation. The signals are produced in the cell and it regulates itself. The processes are M, G1, S and G2. Cytokines regulate the whole process, which cyclins. CDKs are involved. Usually the inhibitors of the cyclins and cytokines prevent proliferation.
HPV affects the non-differentiating keratinocytes to replicate in an unregulated manner. In the upregulation, the host usually acts to prevent proliferation by trying to apoptose cells usually but HPV suppressing the RB gene and phosphorylating this protein and suppressing p53. HPV E6 binds to p53 causes lack of transcription of cell cycle inhibitors. We can vaccinate against this by giving empty capsids, meaning you get the immune response to the virus stopping you from getting it.
Newcastle disease from chickens can cause an 'immunity' to stomach cancer!
Retroviruses cause the responses. However, there can be latency as the virus needs to insert near the gene it wants to activate to cause the change in the cell cycle. For example, if the virus is near c-myc gene this upregulates the gene. It is hard to attribute the cause to a virus.
Tumour associated viruses show us a lot about which genes are essential in cancer.
Novel therapeutic approaches involve vaccines.
Cram notes: Chronic Myeloid Leukaemia
Leukaemia is a cancer of the white blood cells. CML tends to be hereditary.
As this is a chronic disease it is not usually diagnosed until there is:
Splenomegaly,
High white cell count,
Fatigue,
Weight loss,
Sweating,
Anaemia,
Haemorrhage,
Gout,
Retinal haemorrhage
and fever.
Looking at the bone marrow aspirates and trephines you see myeloid hyperplasia and megakaryocytes.
This often occurs as a tanslocation between chromosomes 9 and 22 (BCR-Abl) which is also referred to as the Philadelphia chromosome. There's a fusion protein which causes the Abl gene encoding for tyrosine kinase activity to become activated. This fusion protein is responsible for the CML phenotype. The Bcr-Abl gene has a kinase demain. ATP binds the BCR-Abl and a substrate is phophorylated by the ATP. The substrate is often the beginning of the Ras-Raf-Mek-Mapk signalling pathway. This activates the cell growth and proliferation.
This pathway now has a cure as Imatinib can bind into the same site that the ATP binds into, so no phosphorylation occurs and the Ras pathway is blocked. This is a targetted therapy for this disease.
Unfortunately, imatinib is not curative. However, Human stem cell transplant is. The T cells are destroyed from the person's body, and a new set is infused. This should cure the CML. Imatinib has a few problems; drug resistance and no irradication of stem cell populations. Around 14% of patients are resistant to imatinib. The cells that are reactive to imatinib are eradicated and then the cells left are not affected by the therapy. Mutations in tyrosine kinase mean resistance develops to imatinib.
As this is a chronic disease it is not usually diagnosed until there is:
Splenomegaly,
High white cell count,
Fatigue,
Weight loss,
Sweating,
Anaemia,
Haemorrhage,
Gout,
Retinal haemorrhage
and fever.
Looking at the bone marrow aspirates and trephines you see myeloid hyperplasia and megakaryocytes.
This often occurs as a tanslocation between chromosomes 9 and 22 (BCR-Abl) which is also referred to as the Philadelphia chromosome. There's a fusion protein which causes the Abl gene encoding for tyrosine kinase activity to become activated. This fusion protein is responsible for the CML phenotype. The Bcr-Abl gene has a kinase demain. ATP binds the BCR-Abl and a substrate is phophorylated by the ATP. The substrate is often the beginning of the Ras-Raf-Mek-Mapk signalling pathway. This activates the cell growth and proliferation.
This pathway now has a cure as Imatinib can bind into the same site that the ATP binds into, so no phosphorylation occurs and the Ras pathway is blocked. This is a targetted therapy for this disease.
Unfortunately, imatinib is not curative. However, Human stem cell transplant is. The T cells are destroyed from the person's body, and a new set is infused. This should cure the CML. Imatinib has a few problems; drug resistance and no irradication of stem cell populations. Around 14% of patients are resistant to imatinib. The cells that are reactive to imatinib are eradicated and then the cells left are not affected by the therapy. Mutations in tyrosine kinase mean resistance develops to imatinib.
Cram notes: Colorectal Cancer
Colorectal cancer is the third most common cancer and is the second most common cause of cancer death in this country. It is more common in more developed countries.
There is a familial risk of cancer and there are two main forms:
Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and Familial adenomatous polyposis (FAP).
FAP have mutations in the APC tumour suppressor gene. The clinical pattern is that there are over 100 adenomas in the colon by the age of 30- by 45 they have developed colorectal cancer.
HNPCC is a mutation in mismatch repair. In DNA replication sometimes there are random slips in the bases, in HNPCC there is no mechanisms to correct these slips. MMR mutation can also be indicated in other kinds of cancer. The cancer usually develops in the right side of the colon and there may be a Crohn's type reaction.
The criteria for diagnosis are Bethseda and Amsterdam 1 and 2. Small errors in the genome are not repaired and there tends to be two hits in the MMR gene- MLH1 and MSH2 are usually the ones affected. The chromosomal loss or MMR instability affects many areas.
Inflammatory bowel disease can predispose to cancer. The risk of cancer depends on the duration of time you have had the inflammatory bowel disease. There is an increased risk of 18% after 30 years. Anything that changes the colon cells can promote colorectal cancer.
Risk factors:
Older age
Male
Cholecystectomy
Uretocholic anastamosis
Female hormonal factors
Red meat/Processed meat
Calcium
Sedentary
Obesity
Diabetes
Radiation
Alcohol
History of polyps
Previous colorectal/small bowel/ breast cancer
Colorectal cancer develops in a series of histological stages characterised by mutations in different oncogenes and tumour suppressor genes. For example, hyperplasia, adenoma and then carcinoma. There are usually around 4-6 mutations that occur to develop into a malignancy.
There is a familial risk of cancer and there are two main forms:
Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and Familial adenomatous polyposis (FAP).
FAP have mutations in the APC tumour suppressor gene. The clinical pattern is that there are over 100 adenomas in the colon by the age of 30- by 45 they have developed colorectal cancer.
HNPCC is a mutation in mismatch repair. In DNA replication sometimes there are random slips in the bases, in HNPCC there is no mechanisms to correct these slips. MMR mutation can also be indicated in other kinds of cancer. The cancer usually develops in the right side of the colon and there may be a Crohn's type reaction.
The criteria for diagnosis are Bethseda and Amsterdam 1 and 2. Small errors in the genome are not repaired and there tends to be two hits in the MMR gene- MLH1 and MSH2 are usually the ones affected. The chromosomal loss or MMR instability affects many areas.
Inflammatory bowel disease can predispose to cancer. The risk of cancer depends on the duration of time you have had the inflammatory bowel disease. There is an increased risk of 18% after 30 years. Anything that changes the colon cells can promote colorectal cancer.
Risk factors:
Older age
Male
Cholecystectomy
Uretocholic anastamosis
Female hormonal factors
Red meat/Processed meat
Calcium
Sedentary
Obesity
Diabetes
Radiation
Alcohol
History of polyps
Previous colorectal/small bowel/ breast cancer
Colorectal cancer develops in a series of histological stages characterised by mutations in different oncogenes and tumour suppressor genes. For example, hyperplasia, adenoma and then carcinoma. There are usually around 4-6 mutations that occur to develop into a malignancy.
- k-Ras mutations are found in 35% of cancers as it increases cell growth.
- TGF-B pathways trigger SMAD2/4 which encode proteins that cause apoptosis (chromosome 18)- 60% of colorectal cancer has this. SMAD4 is indicated in juvenile polyposis.
- WNT- B-catenin pathway - B-catenin causes the cell to move into S phase and so there is more proliferation. The WNT usually signals the cell to inhibit APC (TSG) which usually suppresses B-catenin. The lack of suppression leads to the proliferation.
In carcinogenesis there needs to be genomic instability. Normal cells stop moving forward in the cell cycle if there's damage, so losing p53 is very important in lots of cancers invading. The cell cycle retardation is not occuring.
Chemotherapy is used in colorectal cancer. In people around age 60, if less nodes are involved this is much more effective. As there are more nodes involved this becomes less effective. The chemotherapy regime changes from 5-FU. Surgery may be used to try and remove the cancer. However, when it has metastasised this will be less useful.
Cram notes: Tumour Suppressor genes
In cancer TSGs are usually things that negatively regulate the cell cycle preventing growth and delaying division in order to ensure that there is genomic integrity even after genotoxic stress that could be caused by things such as oxygen radicals and carcinogens.
p53 causes apoptosis when there is DNA damage to prevent a damaged cell from replicating. It causes a deregulation of cell growth in order for repair to take place. This is vital in tumours as these things are downregulated so that the tumour develops without these mechanisms suppressing it. The cells can then grow and proliferate in a deregulated manner. Tumour suppressor genes are seen in a 'recessive' pattern in cancer- the mutated cell will have an effect on the cell in a dominant manner- however, until both genes are mutated there will not be deregulation to the point of tumorigenesis. If one is 'knocked out' the other compensates for the regulatory function.
If one mutated allele is inherited, only one needs to be mutated sporadically so in these cases there is usually earlier onset of disease.
TSGs:
p53 - Li Fraumeni Syndrome
RB1 - Retinoblastoma
BRCA1 - Breast cancer
BRCA2 - Fanconi anaemia
APC - Familial Adenomatous polyposis
CHK2 - Li Fraumeni
ATM - ataxia talengesia
VHL - Von hippel landau (phaechromocytoma/ renal carcinoma)
Retinoblastoma is a cancer of the retina, and if RB1 is mutated. 40% of this is familial and will affect both eyes giving a squint and a white reflection. Treatment is lazer therapy or chemotherapy. Around 90% are cured. In familial cases 20% have large mutations in the gene though single base changes account for some cases. RB1 tends to be hypermethylated.
In familial RB there are many people affected in a family.
The RB gene usually functions as a transcription repressor so it usually sits on part of the DNA blocking the transcription. However, in G1 phase it is phosphorylated by cdk4/6 which causes it to uncouple from the DNA, cdk2 and cyclin e also phosphorylate the RB protein at the end of G1 allowing proliferation.
p53 is the most common TSG mutated in cancer. It is considered the 'guardian of the genome'. It protects against the genomic instability. Around 40% of all human cancers carry this defect- it may be much higher than this. Genetically and clinically it presents with 'Li Fraumeni'- there are early onsets of tumours and there are multiple primary tumours. In a family tree many members would be affected. Around 400 families worldwide are affected.
There are different types of Li Fraumeni Syndrome.
LF1 - 70% - mutations in germline p53 on chromosome 17. Sarcomas develop before age 45 and there is usually at least one primary relative with a cancer under the age of 45.
LF2 - p53 (40%) or CHK2 mutations - very early onset. Childhood cancer or brain tumour before 45. Primary or secondary relative with linked cancer.
LF3 - chromosome 1
p53 mutations can lead to cancers of the ovary, oesophagus, lung, head and neck... etc. It is widespread. Loss of p53 usually comes directly before the tumour develops, it's often the last mutation that causes a hyperplastic area and adenoma to become a carcinoma. Carcinomas can invade and metastasise.
The p53 TSG is a tetramer and transcribes proteins that stop the cell cycle. This is usually mediated by ATM and CHK2. These genes usually cause activation of p53 which then causes a feedback loop to mdm2 which inhibits the activation of p53. This is the 'master switch'. p53 can cause apoptosis through the activation of BCL2. When there's cellular stress p53 accumulates and upregulates this protein which causes the cell death. Mutant p53 can't transcribe the molecules that cause cellular senescence, apoptosis, growth arrest and inhibiting angiogenesis. Gain of function mutants have increased drug resistance and these do actually promote genomic instability.
BRCA1 and BRCA2 are indicated in breast carcinoma and ovarian tumours. Around 1 in 100 women have BRCA1 mutations and it accounts for over 60% of inherited breast cancer. Of all breast cancers it is around 5%.
BRCA1 mutation is also associated in prostate cancer. Around 300 different mutations have been described- one is a founder gene in the Ashkenazi jewish population. This gene usually function in DNA damage checkpoint signalling so is involved in the repair process of damaged DNA. BRCA1 can be acted upon by ATM and CHK2 and acts during G2 phase or S phase. In these phases it can cause cell cycle arrest so DNA can be repaired. BRCA2 predisposes to the same tumours as BRCA1 but also has a role in fanconi anaemia. These genes are not very often indicated in breast cancer that is not familial.
BRCA 1 tumours have a higher mitotic rate, BRCA2 tumours have higher tubule formation.
BRCA2 acts with RAD51 in Homologous recombination repair. It is loaded onto the DNA and helps nucleotide filament formation. The major role is to modulate DNA double stranded break repair.
BRCA1 forms an anchor so that RAD50 can act in repair.
p53 causes apoptosis when there is DNA damage to prevent a damaged cell from replicating. It causes a deregulation of cell growth in order for repair to take place. This is vital in tumours as these things are downregulated so that the tumour develops without these mechanisms suppressing it. The cells can then grow and proliferate in a deregulated manner. Tumour suppressor genes are seen in a 'recessive' pattern in cancer- the mutated cell will have an effect on the cell in a dominant manner- however, until both genes are mutated there will not be deregulation to the point of tumorigenesis. If one is 'knocked out' the other compensates for the regulatory function.
If one mutated allele is inherited, only one needs to be mutated sporadically so in these cases there is usually earlier onset of disease.
TSGs:
p53 - Li Fraumeni Syndrome
RB1 - Retinoblastoma
BRCA1 - Breast cancer
BRCA2 - Fanconi anaemia
APC - Familial Adenomatous polyposis
CHK2 - Li Fraumeni
ATM - ataxia talengesia
VHL - Von hippel landau (phaechromocytoma/ renal carcinoma)
Retinoblastoma is a cancer of the retina, and if RB1 is mutated. 40% of this is familial and will affect both eyes giving a squint and a white reflection. Treatment is lazer therapy or chemotherapy. Around 90% are cured. In familial cases 20% have large mutations in the gene though single base changes account for some cases. RB1 tends to be hypermethylated.
In familial RB there are many people affected in a family.
The RB gene usually functions as a transcription repressor so it usually sits on part of the DNA blocking the transcription. However, in G1 phase it is phosphorylated by cdk4/6 which causes it to uncouple from the DNA, cdk2 and cyclin e also phosphorylate the RB protein at the end of G1 allowing proliferation.
p53 is the most common TSG mutated in cancer. It is considered the 'guardian of the genome'. It protects against the genomic instability. Around 40% of all human cancers carry this defect- it may be much higher than this. Genetically and clinically it presents with 'Li Fraumeni'- there are early onsets of tumours and there are multiple primary tumours. In a family tree many members would be affected. Around 400 families worldwide are affected.
There are different types of Li Fraumeni Syndrome.
LF1 - 70% - mutations in germline p53 on chromosome 17. Sarcomas develop before age 45 and there is usually at least one primary relative with a cancer under the age of 45.
LF2 - p53 (40%) or CHK2 mutations - very early onset. Childhood cancer or brain tumour before 45. Primary or secondary relative with linked cancer.
LF3 - chromosome 1
p53 mutations can lead to cancers of the ovary, oesophagus, lung, head and neck... etc. It is widespread. Loss of p53 usually comes directly before the tumour develops, it's often the last mutation that causes a hyperplastic area and adenoma to become a carcinoma. Carcinomas can invade and metastasise.
The p53 TSG is a tetramer and transcribes proteins that stop the cell cycle. This is usually mediated by ATM and CHK2. These genes usually cause activation of p53 which then causes a feedback loop to mdm2 which inhibits the activation of p53. This is the 'master switch'. p53 can cause apoptosis through the activation of BCL2. When there's cellular stress p53 accumulates and upregulates this protein which causes the cell death. Mutant p53 can't transcribe the molecules that cause cellular senescence, apoptosis, growth arrest and inhibiting angiogenesis. Gain of function mutants have increased drug resistance and these do actually promote genomic instability.
BRCA1 and BRCA2 are indicated in breast carcinoma and ovarian tumours. Around 1 in 100 women have BRCA1 mutations and it accounts for over 60% of inherited breast cancer. Of all breast cancers it is around 5%.
BRCA1 mutation is also associated in prostate cancer. Around 300 different mutations have been described- one is a founder gene in the Ashkenazi jewish population. This gene usually function in DNA damage checkpoint signalling so is involved in the repair process of damaged DNA. BRCA1 can be acted upon by ATM and CHK2 and acts during G2 phase or S phase. In these phases it can cause cell cycle arrest so DNA can be repaired. BRCA2 predisposes to the same tumours as BRCA1 but also has a role in fanconi anaemia. These genes are not very often indicated in breast cancer that is not familial.
BRCA 1 tumours have a higher mitotic rate, BRCA2 tumours have higher tubule formation.
BRCA2 acts with RAD51 in Homologous recombination repair. It is loaded onto the DNA and helps nucleotide filament formation. The major role is to modulate DNA double stranded break repair.
BRCA1 forms an anchor so that RAD50 can act in repair.
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