preventing leaking of Cytochrome c from mitochondria] § TP53 & RB suppressor genes – regulate cell cycle (G1 to S phase) [RB – sequester specific transcription factor needed for cell cycle progression; TP53 – inhibits Cdk4 to arrest cell cycle in G1 phase] § Cyclin D binds to Cdk4 (cyclin-dependent kinase 4) forming a complex that phosphorylates RB protein causing the cell to enter S-phase from G1 phase. § Most characteristic features of Apoptosis is peripheral aggregation of chromatin (castrated patient’s prostate cells show apoptosis) § Free radicals cell injury – damage membrane & DNA § Reperfusion injury – reperfusion of ischemic tissue produce superoxide free radicals which irreversibly damage previously injured cells § Intracellular iron produce hydroxyl ions which damage parenchymal cells (cirrhosis in hemochromatosis) § Fatty liver – clear space pushing the nucleus to the periphery (microscopic) § Histamine – vasodilation of arteriole (responsible for redness & heat) § Histamine - ↑ permeability of venules (responsible for edema) § PGE2 (prostaglandin) – sensitize nerve endings causing pain § Neutrophils – primary leukocyte in acute inflammation § Monocytes & Lymphocytes – primary leukocyte in chronic inflammation § Eosinophil – major basic protein § Neutrophil – lactoferin, myeloperoxidase, NADPH oxidase § Selectins – responsible for “rolling” of neutrophils § β 2 integrins – neutrophil adhesion molecule § Leukocyte Adhesion Deficiency – deficiency of selectins or β 2 integrins (CD11a:CD18) – delayed separation of umbilical cord in newborn
S.S.Patel , M.D. © All rights reserved 107 § Amyloid – abnormal folding of protein – structure – beta-plated sheet – apple green birefringence in polarized light – Amyloid light chain (AL) [derived from light chains – eg. Bence Jones protein]; Amyloid Associated (AA) [derived from serum associated amyloid (SAA), an acute phase reactant] ; β -Amyloid (A β ) [derived from amyloid precursor protein (protein product of chromosome 21) responsible for Alzheimer at early age (around 35) in patient with Down syndrome] ■ Important suppressor genes: - p53 (most cancers; chromosome 17) - APC (Familial Polyposis; chromosome5) - BRCA-1 (Breast/Ovarian cancer, chromosome 17) - BRCA-2 (Breast cancer, chromosome 13) - NF-1 and -2 (neurofibromatosis) - Rb (Retinoblastoma; chromosome 13) - VHL (regulate nuclear transcription, Von Hippel-Lindau syndrome) ■ Oncogene relationships: ˗ ERBB2 [ HER ] – codes for receptor synthesis – breast cancer ˗ RAS – codes for Guanosine triphosphate signal transduction (G proteins that transduce signals received from growth factor receptors to the phosphatidyl inositol second messenger system) –30% of all human cancers include cancers of the lung, colon and pancreas as well as leukemia (20-25% of acute myelogenous leukemia) ˗ ABL – produces non-receptor proteins located on the inner cell membrane surface – t9;22 translocation leads to CML ˗ C -myc – is located in the nucleus and produce protein products that activate nuclear transcription – t8;14 translocation leading to Burkitt's lymphoma ˗ N-myc –
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