p53 and Cancer Karina Espinoza Biochemistry 118QWhat is p53? What is p53? A protein found inside cells A stress sensor of signals: -DNA damage-hypoxia-oncogene expression-nutrient deprivation-ribosome dysfunctionIn unstressed cells= p53 is inactiveMDM2 ubiquitin ligase degradation of p53Today’s focus: Today’s focus: stressor DNA damage stressor DNA damage p53 senses damaged DNA aids in regulation of DNA repair p53 = tumor suppressor protein prevents cancer *What is a tumor?-a mass of tissues that result from excessive & uncontrolled cell division (can be benign or malignant)What does p53 do?What does p53 do?p53 has p53 has 22 main functions main functions1. Cell cycle arrest= p53 STOPS cell cycle-until DNA is repairedIs DNA damaged?Is DNA damaged?2. Apoptosis (cell suicide)2. Apoptosis (cell suicide)p53= transcription factorfor 3 pro-apoptotic genesCytochrome c releaseCaspase activation:-cleavage of key cell proteinsthat cause cell deathCancer and p53Cancer and p53p53 prevents cancer (evidence: knockout mice) Inheriting only 1 copy of functional p53 gene= predisposition to cancer (many kinds)“Li-Fraumeni syndrome”Patients have a 50% chance of developing cancer by 30 yrs oldrare condition-Is this the only way that p53relates to cancer?p53 is the most commonly p53 is the most commonly mutated gene in cancermutated gene in cancerP53 has been found to be mutated in more than 52 kinds of cancersHow does a mutation in How does a mutation in p53p53cancer?cancer?*What is Cancer? Uncontrolled growth/proliferation of cells Mutant p53 can NO longer bind to DNA in an effective way= p21 protein is not made= no stop signal for cell division (no apoptosis/arrest)Even if DNA is damaged cell proliferates! = mutations propagate= malignant tumors are formed= cancer With p53 Without p53Failed G1arrestp53+/+ Cell G1 arrested cell(DNA repair)p53-/- CellPropagationof mutationsAdditionalmutationsMalignantcellp53Using what we know about Using what we know about p53p53cancer therapycancer therapyCancers that have a p53 mutation= poor prognosis Why? Tumor cells not likely to undergo apoptosis/cell cycle arrest when damaged by therapy Radiation and chemotherapy may secondary cancersAlternative Treatments: Alternative Treatments: Gene TherapyGene TherapyIntroducing genetic material into cells to compensate for abnormal genes or to make beneficial proteinGene Therapy: GendicineGene Therapy: GendicineChina, 2003 China, 2003 *What is Gendicine? Recombinant Human Ad-p53 InjectionTarget cells: cancer cells (has been FDA approved for neck and head sarcomas)Vector: replication-defective adenovirus Viruses can infect specific cells and deliver their DNA Genetically engineered virus to have p53 gene p53 will be expressed via the host’s transcription and translation processesResults: cancer cured (apoptosis of damaged cells)ReferencesReferenceswww.ncbi.nlm.nih.gov/
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