p53
TRANSCRIPT
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p53 THE TUMOR SUPPRESSOR
Presented bySpoorthi shridhar MSc. biochemistry
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INTRODUCTION
• Tumor Suppressor
• 53 kDa protein
• Encoded by TP53 gene
• Regulates cell cycle
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HISTORY• 1979 - David Lane and Lionel Crawford
• 1983 - The term “p53” was coined
• p53 acknowledged as an oncogene
• 1984 - David Wolf and Rotter
• 1989 - p53 tagged as a tumor suppressor
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STRUCTURE
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AMINO TERMINAL DOMAIN transactivation transcription factors – MDM2
PROLINE-RICH REGION stability
CENTRAL CORE DNA binding domain
C-TERMINAL DOMAIN negative regulation
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STABILITY OF P53
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ACTIVATION
PHYSICAL AGENTS: UV, gamma, X-rays
CHEMICAL AGENTS: carcinogens chemotherapeutic agents alkylating agents
OTHER CAUSES hypoxia heat shock
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FUNCTIONS
activation in response to stress stimuli
prevents inappropriate cell proliferation: cell cycle arrestapoptosis
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CELL CYCLE ARREST IN G1 PHASE
Molecular Biology Of The CellBruce Alberts
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CELL CYCLE ARREST IN G2 PHASE
p53
Gadd 45 CDK1
Cyclin B/CDK1
Prevents phosphorylation
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APOPTOSIS
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MUTATIONS
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LUNG CANCER:
• 33% in adenocarcinomas to 70% in small cell lung cancers
• GC to TA transversions• Exogenous carcinogens such as benzopyrene • Codons 157, 248 and 273
UV AND SKIN CANCERS:
• CC to TT transitions• Codons 245 and 247/248
COLORECTAL CANCER:
• 34% proximal colon tumors• 45% distal colon and rectal tumors
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Molecular Cell Biology
Lodish Et al.
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THERAPEUTIC APPLICATIONS
• Inhibiting interaction of MDM2 with p53
• Small molecule inhibitors: nutlins
• Antisense oligodeoxy nucleotides
• Inhibiting E6 protein of Human Papilloma Virus
• Leptomycin B and Actinomycin D
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• Induction of apoptotic pathways
• Introduction of wt p53 gene into tumors
GENE THERAPY:
• 2004 - treatment of head and neck cancer in China
• McCormick and co-workers, USA - infection of the tumor with recombinant adenovirus.