Assignment 1 tutorial -detailed explanation

Assignment 1 tutorial -detailed explanation

1. Assignment 1 Individual presentations

2. Topics

3. 1. Chronic Myeloid Leukemia (CML) Pathway: BCR-ABL Tyrosine Kinase Signaling Mutation: Formation of the BCR-ABL Fusion Gene Leading to Constitutive Tyrosine Kinase Activity

4. 1. Chronic Myeloid Leukemia (CML) CML is a cancer of the bone marrow caused by a specific chromosomal translocation known as the Philadelphia chromosome, where the BCR gene on chromosome 22 fuses with the ABL gene on chromosome 9. Signaling Mechanism: The BCR-ABL fusion protein possesses constitutive (always active) tyrosine kinase activity, which leads to uncontrolled proliferation of white blood cells by constantly activating downstream signaling pathways like RAS/MAPK and PI3K/AKT. Clinical Implication: This constant signaling is a hallmark of CML, making it sensitive to tyrosine kinase inhibitors (TKIs) like Imatinib, which target the BCR-ABL protein.

5. 2. Type 2 Diabetes Mellitus Pathway: Insulin Receptor Signaling Pathway Mutation: Mutations Affecting Insulin Receptor Substrates

6. 2. Type 2 Diabetes Mellitus Type 2 Diabetes is characterized by insulin resistance, where the body's cells fail to respond appropriately to insulin. Signaling Mechanism: Insulin binds to its receptor, activating the PI3K/AKT signaling pathway, which facilitates glucose uptake by cells. Mutations in insulin receptor substrates (IRS) or defects in downstream signaling can impair this process. Clinical Implication: This results in high blood glucose levels and diminished glucose uptake by muscles and other tissues, contributing to the long-term complications associated with diabetes.

7. Activation model for the insulin receptor https://www.nature.com/articles/s12276-023-01101-1

8. 3. Breast Cancer (HER2 Positive) Pathway: HER2/Neu Receptor Tyrosine Kinase Signaling Mutation: Overexpression of the HER2 Gene Over two million new cases of BC were diagnosed in 2018 worldwide according to the World Health Organization

9. 3. Breast Cancer (HER2 Positive) HER2-positive breast cancer is a subtype driven by the overexpression of the HER2 (human epidermal growth factor receptor 2) gene , leading to enhanced cell division and survival. Signaling Mechanism: The HER2 receptor is part of the ErbB family of receptor tyrosine kinases. Overexpression results in continuous signaling through pathways like PI3K/AKT and RAS/MAPK, promoting tumor growth. Clinical Implication: Therapies like Trastuzumab (Herceptin) target the HER2 receptor to block its activity, slowing the progression of HER2-positive breast cancer.

10. 4. Non-Small Cell Lung Cancer (NSCLC) with G12C Mutation Pathway: RAS/MAPK Signaling Pathway Mutation: Aberrant Activation of the RAS/MAPK Pathway Due to G12C Mutation

11. 4. Non-Small Cell Lung Cancer (NSCLC) with G12C Mutation The G12C mutation in the KRAS gene is a specific driver mutation in NSCLC, resulting in the substitution of glycine with cysteine at position 12. Signaling Mechanism: KRAS is a small GTPase involved in the RAS/MAPK pathway. The G12C mutation locks KRAS in its active GTP-bound form, leading to continuous cell division and tumor growth. Clinical Implication: Recent breakthroughs in targeted therapy, such as KRAS G12C inhibitors (e.g., Sotorasib ), have shown promise in treating this previously untreatable mutation.

12. The three most common hotspots involve codons 12, 13 and 61. Mutations in any of these codons lead to an accelerated exchange of nucleotides, and/or a decrease in the binding of GAP. Either of these increase GTP binding and KRAS activation.

13. 5. Cystic Fibrosis Pathway: CFTR Channel Regulation of Chloride Ions Mutation: ΔF508 Deletion in the CFTR Gene

14. 5. Cystic Fibrosis Cystic fibrosis is caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, with the ΔF508 deletion being the most common. This leads to the production of a defective CFTR protein. Signaling Mechanism: The CFTR protein functions as a chloride ion channel. The ΔF508 mutation causes improper folding of the CFTR protein, preventing its transport to the cell membrane and disrupting chloride and water transport across epithelial cells. Clinical Implication: This results in thick mucus buildup in organs like the lungs and pancreas. Treatments now include CFTR modulators, which attempt to correct the defective protein folding and trafficking.

15. 5. Cystic Fibrosis https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(12)00038-X

16. 6. Alzheimer's Disease Pathway: Amyloid Precursor Protein (APP) Processing and Tau Phosphorylation Pathways Mutation: Mutations in APP, PSEN1, or PSEN2 Genes

17. 6. Alzheimer's Disease Alzheimer’s disease is a neurodegenerative disorder marked by the accumulation of amyloid-beta plaques and neurofibrillary tangles made of hyperphosphorylated tau proteins. Signalling Mechanism: Mutations in APP (amyloid precursor protein), PSEN1, or PSEN2 disrupt the normal processing of APP, leading to increased production of amyloid-beta peptides. This leads to neuronal damage. Additionally, dysregulation of tau protein phosphorylation contributes to tangle formation. Clinical Implication: Therapies are in development targeting amyloid-beta and tau pathways, with recent breakthroughs like Aducanumab, a monoclonal antibody targeting amyloid plaques, providing potential treatment options.