4.26.2010 2
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4.26.2010 2 4.26.2010 2 Document Transcript

  • 4.26.2010 – Cancer<br />
    • Mutations
    • Most mutations occur after birth
    • Environmental mutations
    • P53 – prevents DNA damage or drives apoposis
    • No safeguards now to recognize damage and shut cell proliferation down
    • Benzoapyrene from smoking
    • Deamination
    • Replace for thymine –
    • Andogenous process – liver metabolism
    • About 50% of cancers are from a mutation in the p53 gene
    • P53
    • Tumor suppressor gene (not a protooncogene)
    • Helps suppress cell proliferation that is abnormal
    • Retinoblastoma – RB
    • Holds on to and inhibits transcription factors that drive production of cyclins that move past G1 until phosphorylated by Ras pathway for gene transcription regulation
    • Restricts mitosis and regulates cell growth in unaltered state
    • Proto-oncogenes
    • APC
    • Ras (ras pathway)
    • In an overexpressed state, will drive
    • Src – SH2 domains
    • Kinase, has SH2 domain, activated in response to RTK
    • If there is is single allel in a protooncogene that is mutated, it will cause that cell to divide uncontrollably and unregulated
    • If there is a normal copy on the other allele, a normal cell will divide correctly. However, if both alleles are mutated, that single cell may divide uncontrollably.
    • Pathways
    • Ras
    • GFs activated RTK
    • Recruit SH2 to activate Ras
    • Ras activates gene transcription pathways
    • Myc, when Pi, will lead to enhanced gene expression and enhance cell mitosis
    • Protonocogene – leads to favored gene expression and poliferation
    • P16, like p21, inhibits cyclin that binds to cyclin and keeps it from Pi Rb
    • P16 is a tumor suppressor, restricts cell mitosis
    • Anti growth factors
    • TNS – tumor necrosis factor
    • Growth factor that regulates growth – restricting it
    • Activates a pathway that turns on inhibitors of cyclins
    • Binds to RTK
    • Attacks
    • Secreted by activated immune cells
    • P53
    • Upregulates p21 function
    • Drives inhibits cyclin dependent kinases and cells stop dividing – senescence – G0
    • PUMA
    • Activated by p53 that leads to cells death
    • Inhibits Bcl2
    • Makes mitochondrial membrane more unstable
    • Cytocochrome c is released
    • Apotosome and caspase 9
    • Apoptosis
    • Checkpoints within mitosis
    • What is regulating G2 and metaphase checkpoints and drive to S phase and see what is required and see if they act as tumor suppressors or proto oncogenes
    • Examples of Oncogenes
    • GFs
    • Overexpression can cause cancers
    • PDGF – platelet derived growth factor
    • Sarcomas
    • Fibrosarcomas
    • There are two genes (oncogenes) that express amounts of PDGF
    • V-sis
    • TRK receptor
    • Binds to JrK – Nerve Growth factor, neurotrophins, brain derived nuerotrophic factor (BDNF)
    • Thyroid
    • Breast
    • Ras – inability to hydrolzyze GTP to GDp – making it on all the time
    • Single point mutations
    • Raf
    • Src kinase – v-src – sarcomas
    • Myc – regulated by ras – translocation, aplification, inserional mutagensis – 3 types of cancer
    • Cyclins – Bcl2 –
    • Types of Cancer
    • Carcinomas – Epithelium
    • Throat lining, skin, intestines
    • Sarcomas
    • Muscles or Connective Tissue
    • Leukias/Lymphomas
    • Hematopoietic System
    • Nervous System
    • Neuromas
    • Gliomas
    • Astrocytomas
    • What types of Mutations are taking place?
    • Gene amplification
    • Some muation has caused gene to be respresnted in multiple ways, causing an overexpression of that gene product
    • Chromsomes rearrangement
    • Overexpression of proteins that enhance production of that particular gene of interest
    • Fusio nevent – gene made is on all the time
    • Her2 receptor
    • Single mutation in transmembrane region
    • Thinks bound to GF
    • Deletion – receptor is always on signaling for cell to divide
    • TRK receptor
    • RTK, bound by GFs, autphosphorylation
    • Mutations: gene rearragnement replaces EXdomain of receptor ith a muscle tropomysoin protein involved in smooth muscle contraction, losing resulatory EXC domain and TRPM is sticking out.
    • Links with trasmembrane