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الله فتبارك
الخالقين احسن
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p53 Structure, Function and Therapeutic Applications
Provider: Dr.Davood Nourabadi(PhD,medical physiology)
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Common names
• p53• cellular tumor antigen p53• phosphoprotein p53• tumor suppressor p53• Tumor protein p53
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Discovery• Identified in 1979 • The TP53 gene from the mouse was first cloned in 1982.• The human TP53 gene was cloned in 1984 and the full length clone in
1985.• In 1991-92 reported that TP53 was a critical part of a signal transduction
pathway that helped cells respond to DNA damage.• in1992THE GUARDIAN OF THE GENOME” by Nature magazine.
• In 1993, p53 was voted MOLECULE OF THE YEAR by Science magazine.
• In 1993 discovered p21(WAF1) as a gene regulated directly by p53.• Presently, p53 is known to play a key role in practically all types of
human cancers, and the mutation or loss of the p53 gene can be identified in more than 50% of all human cancer cases worldwide.
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Cloning of the p53 gene, followed by successive
experiments showed that it is actually a
tumor suppressor geneMoshe
OrenArnold Levine
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Genea 20-Kb gene containing 11 exons and 10 introns,which is located on the small arm of chromosome 17.This gene belongs to a highly conserved gene familycontaining at least two other members, p63 and p73.one of the most frequently mutated gene in human cancers
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p53 protein
• 393aa• MW:43.7 KDa• Gene: TP53• p53 belongs to an unique protein family
which includes three members: p53, p63 and p73.
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Cont..• p53 seems to have evolved in higher
organisms to prevent tumor development, whereas p63 and p73 have clear roles in normal developmental biology they show considerable homology with p53. all three of these proteins can induce apoptosis
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53 K
61 2 3 4 5
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• p53 have 7 domain include:
1. An acidic N-terminus transcription-activation domain (TAD) or activation domain 1 (AD1)
2. Activation domain 2 (AD2)
3. Proline rich domain
Structure of p53
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4. Central DNA-binding core domain (DBD)most highly conserved region
5. Nuclear localization signaling domain(NLS)
6. Homo-oligomerisation domain (OD)
7. C-terminal
Cont...
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Various intracellular and extracellular stimuli
• DNA damage (ionizing radiation, UV radiation, application of cytotoxic drugs or chemotherapeutic agents, and infectious virus)
• Heat shock• Hypoxia• Oncogene overexpression
p53 is activated and triggers diverse biological responses, both at the level of a single cell as well as in the whole organism
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• Damage to DNA: activation of protein kinase including ATM (Ataxia telangiectasia mutated) and ATR (Ataxia telangiectasia and Rad3-related), that enzymes phosphorylate of p53 activated CDKN1A gene production p21
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• In response to various types of stress, p53 is accumulated in the nucleus and binds to specific sites in the regulatory regions of p53- responsive genes, and then strongly promotes the transcription of such genes
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The regulation of p53 level and activity
• Under normal circumstances, wt p53 is maintained at very low concentrations within the cells and exists mainly in an inactive latent form.
• In normally growing cells, the half-life of p53 is limited to minutes, whereas cellular stress or exposure to DNA damaging agents prolongs it to hours
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Activated genes by p53 include:• Genes involved in cell cycle arrest• DNA repair• Apoptosis• Senescence-related genes, such as genes for p21Waf1/Cip1, Gadd45 (growth arrest and DNA-damage inducible protein 45)
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Genes which may be repressed by p53
• bcl-2• bcl-X • Cyclin B1• MAP4• Survivin
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p53 locating at the crossroads of complex networks of stress response pathways
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Function of p53
Its anti-cancer role, p53 works through several mechanisms:•It can activate DNA repair proteins when DNA has sustained damage.
•It can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition.
•It can initiate apoptosis, the programmed cell death, if DNA damage proves to be irreparable.
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Cell-cycle regulation by p53• p53 can induce cell cycle arrest in the G1, G2 and S
phases of the cell cycle it provides additional time for the cell to repair genomic damage before entering the critical stages of DNA synthesis and mitosis.
• Cyclin-dependent kinase (CDK) inhibitor, p21 is perhaps the best known downstream target of p53 among the various p53 target gene products identified.
• p21 binds cyclin-CDK complexes.
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p53
Cell cycle control involves several checkpoints and checkpoint (molecular breaking) mechanisms
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p53 pathways
MDM2: murine double minutewhich in humans is identified asHdm2
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Induction of apoptosis• Apoptotic gene: products of these genes may
induce apoptosis through either an extrinsic pathway or an intrinsic pathway, namely the death receptor pathway and the mitochondrial pathway, respectively.
It has been suggested that the intrinsic apoptotic pathway is primarily utilized in p53-mediated apoptosis, whereas the extrinsic pathway is used to augment the apoptotic response.
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•The intrinsic apoptotic pathway is engaged when cells are challenged by stress and is dominated by the Bcl-2 family proteins. In the regulation of the intrinsic pathway, pro-apoptotic
• gene products such as Bax, Bid localize to the mitochondria and promote the loss of mitochondrial membrane potential and release of cytochrome c, resulting in the formation of the apoptosome complex with Apaf-1 and caspase 9.
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• In cell death extrinsic pathway, p53 can promote apoptosis through activation of the death receptors located at the plasma membrane and lead to inhibition of the production of IAPs (inhibitor of apoptosis proteins).
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Therapeutic applications of p53 • p53 can be a useful biomarker in carcinogenesis.• useful in studying the efficacy of chemopreventive
agents• p53-MDM2 interaction as the basis of a drug
development strategy.
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