L44: Cancer Biochemistry I-II Flashcards
List the six acquired capabilities of cancer cells
- Self-sufficiency in growth signals - Insensitivity to anti-growth signals - Evading apoptosis - Limitless replicative potential - Sustained angiogenesis - Tissue invasion and metastasis
Define proto-oncogene. How does mutation in these genes contribute to development of cancer?
- Proto-oncogene: promote cell growth - Loss of function causes excessively active growth promotion = stuck accelerator = oncogene = typically dominant mutations
Define tumor suppressor. How does mutation in these genes contribute to development of cancer?
- Tumor suppressor: inhibit cell growth - Loss of function relieves growth inhibition = non-functioning brake pedal, typically recessive mutations
Define caretaker gene. How does mutation in these genes contribute to development of cancer?
- Caretaker genes: maintain integrity of genes (mismatch repair etc.) - Loss of function allows mutations to accumulate
Describe how the receptor tyrosine kinases HER2 and ErbB1 can be converted into constitutively active forms that function as oncoproteins
- HER2 (aka Neu): point mutation allows activation of kinase in the absence of ligand - ErbB1: deletion of ligand bind domain results in constitutive activation of kinase domain
Outline the Ras/MAP kinase pathway and describe how mutant forms of Ras can contribute to the development of cancer.
- Mutations at AA 12, 13 and 61 cause Ras protein that favors GTP binding and therefore an activated form of Ras. - As a result, Ras signaling through Ras/MAP kinase pathway will occur irrespective of ligand binding
What is Burkitt’s Lymphoma? Describe biochemistry that causes it.
- Translocation event moves c-myc gene from normal position on c/s #8 over to c/s #14 - Result = myc gene is now near control elements of antibody HC and continuous production of high levels of Myc occurs in B-cells. B-cells become cancerous
What is the two hit model? Describe this model in relation to the development of retinoblastoma. What is the normal function of Rb?
- Tumor suppressor genes inhibit proliferation - Damage to both alleles must occur to allow unregulated proliferation as the genes are recessive - This is why it is called two hit model - Individuals inheriting one mutant allele of tumor suppressor gene are at increased risk for certain cancers. If somatic mutation in second allele, tumor growth will occur Retinoblastoma mutation: - Rb protein is phosphorylated by cyclin D-CDK4/6 or cyclin E-CDK2. When phosphorylated, drives cell cycle. - Inherited form: one mutant allele from parent, somatic mutation of second allele in retinal cell leads to retinoblastoma. Tumor tends to develop in infancy - Sporadic form: two separate somatic mutations in a retinal cell or its progeny produces retinal cell in which both copies of functional Rb are lost - Symptoms: Leukocoria = white pupil, represents calcified intraorbital masses
Describe role of p53 in triggering cell cycle arrest or apoptosis in response to DNA damage. What gene encodes it?
- p53 is normally an unstable protein, is ubiquinated and destroyed by proteasome when not stabilized - Phosphorylation by ATM/ATR (double-stranded breaks or UV damage respectively) increases stability of it, which leads to transcriptional control of many genes that regulate cell cycle arrest, repair of DNA and apoptosis - Encoded by gene TP53 - Active p53 is homotetramer. Missense mutations in one allele greatly reduce function. Any subunit mutation of the tetramer will cause aberrant function. Mutations act as dominant negative
What is Li-Fraumeni syndrome?
- Dominant heritable condition conferring increased susceptibility to many forms of cancer as a result of dominant negative effect of mutation to TP53 allele - Cells with damaged DNA are free to continue to divide and tumors develop
Describe biochemistry behind HPV-induced cervical cancer
- HPV virus produces E6 and E7 proteins that target p53 and Rb respectively leading to ubiqutination
What is neurofibromatosis I? What is normal function of the protein?
- Symptoms/signs: café au lait spots, multiple non-malignant peripheral nerve tumors (neurofibromas) and iris Lisch nodules - Result of loss of function mutation in NF1 gene (recessive) that encodes neurofibromin that normally accelerates rate of GTP hydrolysis by Ras, causing it to be in inactive form - Lack of NF1 gene function prolongs Ras signaling increases proliferation through MAP kinase pathway
Examples of caretaker genes. Cancers resulting in defects from these genes
- MSH2 or MLH1 code for DNA mismatch repair. Mutations lead to HNPCC: hereditary nonpolyposis colorectal carcinoma - BRCA1 or BRCA2 gene code for machinery involved in homologous recombination. Mutations lead to increased risk of breast/ovarian and cancer development. Unable to repair of double-stranded DNA breaks.
How can epigenetic changes contribute to the development of cancers? Example
- Increased methylation silences transcription of a gene, reducing tumor suppressor expression - Decreased methylation activates transcription of a gene, increasing production of oncoprotein - Example: INK4 promoter methylation suppresses transcription, preventing p16ink4 synthesis, allowing for continued phosphorylation of Rb by cyclin-D:CDK4/6 and cell proliferation
Describe the breakage/fusion/bridge cycle that can occur in cells where there is damage to the cell cycle checkpoints.
- Loss of p53 function prevents ability for cell cycle to arrest - Result = breakage/fusion/bridges in genetic material result in large amount of genetic rearrangement - Normally cells die as a result of this - In the case of cancer, re-expression of telomerase allows cells to continue one with significantly altered DNA
