Cells and molecular biology of cancer Flashcards
Why does cancer occur?
Due to genetic mutations where there is an imbalance between cell death and cell differentiation
What are the features of cancer?
Evades apoptosis
Self sufficiency in growth signals
Sustained angiogenesis
Unlimited replication
Metastasis
Insensitive to tumour suppression signals
Reprogramming
Energy metabolism
What is oncogenes?
Promote progression through the cell cycle.
It only requires one hit to become mutated, and produce a strong proliferation signal for cells to undergo excessive cell growth and form a tumour.
What are the challenges of the cell cycle?
Ensuring there is cell fidelity (same information) and equally passed between the two daughter cells.
What are the cell cycle phases?
M, G1, S, G2 and G0
Cells with a high turnover such as the bone marrow, have a short interphase.
What is G1 phase?
Replication of organelles and proteins
What is G1-CDK?
Growth dependent CDK protein which promotes DNA replication for transition of cell from G1-> S phase via positive feedback loop.
Pathway for G1-CDK?
G1-CDK phosphorylates RbE2f-> Rb + E2f to free E2f for DNA synthesis
What occurs in G2 phase?
Cell grows in size, produces proteins and reorgansies to prepares for cell division
How is DNA synthesised?
Activation of E2f transcription factor for encoding DNA replication proteins
What regulates DNA synthesis?
Retinoblastoma (Rb) protein which is a tumour suppressor gene part of the G1 checkpoint that regulates the E2f transcription factor for S phase entry and cell growth. It is mutated in retinoblastoma cancer.
Which cells do not enter cell cycle?
Neurons and cardiac myocytes
Which cells in the body take the longest time to complete cell cycle?
Liver which takes 1 year
How long is the cell cycle of cancer cells?
12-24 hours
What regulates the cell cycle?
Cyclin-dependent kinases (CDK) that activate proteins via phosphorylation to allow cells to pass to the next stage of the cell cycle. In order for CDK to be functional, it requires binding by cyclins to be activated and form cyclin-CDK complex.
CDK is a serine-threonine kinase.
This is regulated by CDK inhibitors and phosphatases.
What triggers mitosis?
M-CDK protein which induces assembly of the mitotic spindle for chromosomes to attach. Uses phosphorylation process to cause chromosome condensation and nuclear envelope breakdown
What triggers DNA replication in S phase?
S-CDK which phosphorlyates proteins for DNA replication
What are the cell cycle checkpoints?
G0 -> G1
G1 -> S
G2 -> M
M-> G1
What is the G0 -> G1 checkpoint?
Monitors tissue damage and cells required via growth factor signalling
What is the G1 -> S checkpoint?
Restriction point for any DNA damage, environment favourable in nutrients and if cell is large enough.
This is regulated by Rb protein, which is bound to the E2f transcription factor and requires phosphorylation to be free and allow cell cycle progression.
What is the G2-> M checkpoint?
Check DNA post-replication and if environment is still favourable.
What is the M-> G1 checkpoint?
Mitotic assembly checkpoint to see if chromsomes are aligned
What are the signal controls of the cell cycle?
External signals from growth factors and internal signals which nvolve the signal transduction pathway
What are the external signals of the signal transduction pathway?
Growth factor binds to G protein coupled membrane receptor and via signal transduction of kinases, acts on DNA binding proteins
Pathway for cell cycle arrest following double stranded DNA damage?
ATM -> p53 -> p21 which INHIBITS G1-CDK
ATM -> CHK2 (checkpoint kinase 2) which phosphorylase p53 to activate it to INHIBITS CDC25 for preventing the upregulation of G1-CDK
Pathway for repair of double stranded DNA?
ATM -> BRCA for DNA repair
What happens when double stranded DNA strand breaks?
Activation by ATM (ataxia telangiectasiasa mutated protein which is a serine kinase that phosphorylates p53 for checkpoint inhibition. It works with BRCA to repair DNA damage.
What is p53?
Tumour suppressor gene for DNA damage checkpoint to intiaite DNA repiar or cell apoptosis in G1/S which is mutated in cancer. It is phosphorylated by ATM protein when double stranded DNA is damaged.
What is puma protein?
p53 protein upregulated modulator of apoptosis. It transuduces apopototic signals to the mitochondria via activation of BCL2 proteins like Bax and Bad that create pores which cause the release of cytochrome C.
What is p21?
Cycline dependent kinase inhibitor activated by p53
Pathway for cell cycle arrest of single stranded DNA damage?
ATR -> CHK2 which inhibits CDC25 for upregulation of G1-CDK
OR
ATR -> p53 -> p21 which inhibits G1-CDK
Pathway for single stranded DNA repair?
ATR -> BRCA
What is CHK2?
Checkpoint kinase protein which is phosphorylated by ATM protein when double stranded DNA is damaged to activate p53 via phosphorylation to inhibit:
—>CDC25 for G2-> M phase
—> prevent activation of G1-CDK.
What happens when single stranded DNA strand breaks?
Activated by ATR, a serine kinase which is a signal transducer which phosphorylates CHK1 to induce checkpoint inhibition
What is CHK1?
Checkpoint kinase protein for the G2/M phase by activating p53. It is phosphorylated by ATR when single stranded DNA is damaged or there is replication stress.
What is CDC25?
Cell division control protein for G2/M phase, inhibited by CDK1/2
What are the effectors in DNA damage?
Apoptosis, DNA repair or cell cycle arrest.
ATM/ ATR gene mutation
Increases risk of breast cancer and promyelocytic leukemia.
CHK1/ CHK2 mutation
Promotes tumour growth and anti cancer therapy resistance.
G1-CDK mutation
Cyclin is overexpressed in tumours, causing excessive formation of C-CDK complexes which promote cell cycle progression and tumour growth.
Which genes are commonly mutated in cancer?
Encodes for p53 and Rb/e2f
What are the cancer critical genes?
Tumour repressor genes and oncogenes
What are oncogenes?
Genes which prioritise proliferation of cell and its survival. They can become mutated and upregulate tumour formation and growth.
The most common oncogene is RAS.
What do oncogenes code for?
PDGF growth factor and growth factor receptor,
Cell cycle regulator CDK4
Transcription factors MYC
Non receptor protein kinase BRAF
G protein RAS
What is BRAF?
Protein kinase involved in signal transduction pathway for cell proliferation
mutation is associated with ovarian and breast cancer and prostate in men.
What is MYC?
Transcription factor that is a proto-oncogene which is involved in cell cycle progression and apoptosis.
Mutation that causes excess MYC is associated with Burkitt Non-Hodgkin Lymhoma. This cancer is also associated with Epstein-Barr virus.
What is ERBB2?
Pro-oncogene that is a Growth factor receptor which encodes for HER2 and is overexpressed in invasive breast carcinoma
What is a proto-oncogene?
Non-mutated form of oncogene which assists cell division and prevents cell apoptosis.
Why does a proto-oncogene occur?
Normal cell is mutated which results in excessive amounts of normal protein via:
translocation
gene amplification
chromosomal translocation
DNA rearrangement
Insertional mutagenesis
What is Ras protein?
G protein proto-oncogene involved in signal transduction for growth and proliferation. It relies on activation with GTP.
Mutation is associated with pancreatic cancer.
WHat is BCL2?
Protein which regulates apoptosis
How are tumour repressor genes inherited?
It initiates apoptosis or cell cycle inhibition. Mutation of both allele promotes cancer. If only one mutant allele is inherited, the mutation of the other allele is required for cancer risk to increase.
What are the tumour repressor genes?
p53, RB, BRCA1/BRCA2 and Caretaker proteins
What is retinoblastoma?
Cancer in retina cells where genes needed for S phase are not transcribed due to Rb/e2f mutation. Rb/e2f is controlled by G1-CDK phosphorylation. This occurs most commonly in younger children.
What is aneuploidy?
Abnormal chromosomes in haploid set due to p53 mutation that allows damaged DNA replication
How does cell cycle arrest occur?
ATM activates -> p53 which activates -> p21 which inhibits CDK-cyclin to prevent Rb protein phosphorylation
How does cell apoptosis occur?
ATM activates p53 which activates -> puma which inhibits BCL2
What is the most common cause of cervical cancer?
HPV infection of epithelial cells which causes E6 and E7 oncogenic protein production for tumour formation. The tumour has HPV DNA inserted
What is the role of E6 in HPV?
Ubiquitinates p53 to prevent apoptosis
What is the role of E7 in HPV?
Binds to Rb to prevent regulation of checkpoint at G1-> S.
Why does colorectal cancer occur?
—>First hit mutation of APC
—>Second hit mutation of K-RAS which leads to adenocarcinoma formation
—>There is subsequent mutation of DCC and p53 to cause carcinoma formation
Why does obesity promote cancer?
High levels of insulin and IGF-1 for tumour development
Chronic inflammation
High oestrogen
What is the pathway for apoptosis following DNA strand break?
ATM is released which causes activation of p53 via phosphorylation.
P53 will activate puma protein to inhibit BCL2 and allow apoptosis to occur.
What regulates apoptosis?
BCL2 family, which inhibit apoptosis from occurring. This is blocked by puma protein.
What stimulates apoptosis?
BCL-2 associated protein Bax
BCL assoicated protein Bak.
–> They form pores in the mitochondria that cause the release of cytochrome C.
What is the intrinsic pathway for apoptosis?
When the cell is damaged beyond repair, p53 produces BCL2 sensors to recruit BCL2 proteins Bax and Bad to cause damage to the mitochondria of the affected cell. The mitochondria release Cytochrome C.
Cytochrome C and Apaf1 activate the caspase enzym,e, which digests the cellular components and causes damage, making the cell blob and inducing uptake by macrophages.
What is the TRK oncogene?
Tyrosine kinase which upregulates cellular proliferation.
Mutation where there is inversion can lead to thyroid cancer.
