Lecture 47-48 Flashcards
Evidence for monoclonality of Cancer
- Examination of X-inactivation pattern
- usually all tissue are mosaic for X-inactivation, but all cells from cancers have same copy of X inactivated. - Chromosomal abnormalities of cancer
- Once chromosomal aberration (translocation) occurs, then cancer develops then, all cancer cells contain the aberration. - Normal B-cell produce polyclonal Ig , but multiple myeloma (malignant B-cell) produce the same antibody molecule (Monoclonal Ig)
Difference between oncogene and protooncogene
Protooncogene is normal state, but if there is mutation in protooncogene, it becomes oncogene.
(Mutation in one copy is sufficient to cause cancer - gain of function)
Major cell proliferation pathway
MAP (Mitogen-activated protein pathway)
Describe MAP kinase pathway
major cell proliferation pathway
- Growth factor binds to tyrosine kinase receptor.
- Then, dimerization and phosphorylation of activation lip tyrosine
- Phosphorylation of additional tyrosine residue, which leads to activation of Ras-GTP
- Ras-GTP activates Raf (MEKK)
- Raf activates MEK, which activates MAPK. (Phosphorylation of serine/threonine residue)
- MAPK activates DNA-binding proteins which in turn activate gene expression to drive DNA replication and cell division.
Type of mutation in MAP kinase pathway (4)
1.Constitutive activation of receptor
truncation(deletion) or point mutations at GF receptor which cause constitutive activation= self-sufficiency = dimerzation occur without ligand binding
- Activation of myc
- Burkitt Lymphoma
- Translocation between chromosome 8 and 14 occur. So, myc on chr8 fuse to immunoglobulin locus at chr 14. Since myc is now under regulation of IgH promoter, level of oncogene expression increase, and due to rapid cell division caused by myc, lymphocyte fail to differentiate. = - Bcr-Abl Translocation
- Chronic Myeloid leukemia
- Translocation between chromosome 9 and 22, forming philadelphia chromosome (fusion oncogene)
- Hybrid bcr-abl fusion protein is an unregulated cytosolic tyrosine kinase, so abl is stuck in its active form. - Mutation in Ras protein - single point mutation at Gly12 or Gln 61
- Mutation inhibit GTPase activity of Ras, making Ras constitutively active
What is Myc?
nuclear transcription factor important for G1/S transition., stimulate cell cycle
What is abl
Cytoplasmic tyrosine kinase (MAP kinase pathway)
Imatinib mesylate
a powerful tyrosine kinase inhibitor specific for a few tyrosine kinases including bcr-abl, which inhibit constitutively active tyrosine kinase by binding to active site of fusion protein.
What is Ras
It is a GTPase involved in MAP kinase pathway.
It is activated by binding GTP.
- It is inhibited by intrinsic GTPase activity (GTP>GDP).
What is double minutes and its relation to oncogenesis
Double minutes are extrachromosomal fragments of DNA containing an amplified oncogene (multiple / hundreds of copies of oncogene)
- seen in aggressive tumors
What is homogenously staining regions (hsr)
HSR of abnormal chromosome contain amplified oncogenes (multiple/hundreds of copies of oncogene)
Difference between double minutes and homogenously staining regions
Double minutes extrachromosomal fragments of DNA that contain amplified oncogenes, while homogenously staining regions are amplified oncogenes that are attached to chromosome.
Cause of Wilms Tumor
Results form loss-of-function in WT1 on chromosome 11
- Autosomal dominant inheritance, but actually recessive at cellular level, but dominant in pedigree
Difference between familial and non-familial (sporadic) cancer
Familial
- multiple tumors and bilateral
- present at an earlier age
- family history present
What is two-hit hypothesis of sporadic cancers and familial cancer.
For sporadic cancer, 1st mutation in tumor suppressor gene occur (1st hit)
2nd mutation in same gene should occur (2nd hit) for cancer and tumor initiation
For familial cancer, first mutation (1st hit) is inherited thus present in every cells. So second mutation (2nd hit) can occur in any cell, thus only one more hit is needed for tumor initiation.
Relationship between two-hit hypothesis and loss of heterozygosity (LOH)
When there is 2nd hit, it results in loss of heterozygosity (usually due to deletion of normal allele and left with mutant allele only)
Machenisms producing 2nd hit of two-hit hypothesis
- Loss through non-disjunction
- Mitotic recombination
- Gene deletion
- Point mutation
- Methylation (epigenetics)
How is Rb protein regulated?
Cyclin D/Cdk 4,6 hyperphosphorylates Rb thus not bound to E2F. So E2F can activate S-phase genes»_space; cell division
When there is no cyclin D/cdk, Rb is hypophosphorylated, thus bound to E2F. E2F still binds to DNA, but recruits histone methyl transferase and histone deacetylase, blocking transcription.
4 mutations that can lead to dysregulation of G1-S checkpoint
mutation in these 4 genes
- CDKN2A gene (p16) : CDK Inhibitor
- cyclin D gene : complex with cdk inhibit Rb by phosphorylating it
- cdk4 gene :complex with cyclin inhibit Rb by phosphorylating it
- Rb gene : when hypophosphorylated, inhibit E2F thus block transcription
Mutation of Rb gene on chromosome 13 leads to which disease condition?
Retinoblastoma (a childhood cancer)
What disease is caused by inherited mutation in p16 (CDKN2A)?
malignant melanoma
Role of p53 in signaling through G1 checkpoint
when there is double strand break in DNA, ATM and ATR (DNA damage signals) activate Chk1 and 2, which phosphorylates serine residue of p53. P 53 induce either G1 phase arrest or cell apoptosis.
3 roles of p53
- Slows cell cycle for repair (G1 arrest)
- Increase DNA repair capability
- If damage is too great, initiate apoptosis and eliminate cell
