role of p53 gene
TRANSCRIPT
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Activity of p53 in Cancer Progression and metastasis
ByAshish Kumar
M.Tech 1st year
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OUTLINE
• CANCER Introduction• Structure of p53• Function of p53• Literature Review• Conclusion• References • Summary • Questionnaire
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Objective
• To give knowledge of cancer along with brief description of p53 gene
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Current Scenario
• In 2012, an estimated 14.1 million new cases of cancer occurred worldwide.
• Out of 10 deaths 4 from cancer• There are 100 different forms of cancer.• Most common types of cancer are lung, breast, bowel and
prostate which accounts for 4 death in 10 cancer patients• Lung cancer is common in Men’s and Breast cancer in Female
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Cancer
• Single type of cell proliferate continuously becomes immortal further into a tumor.
• Two types of tumor– Benign Tumor– Malignant Tumor
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Who controls cancer in our body?
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p53 Gene
• "the guardian of the genome" • TP53 gene is located on the short arm
of chromosome 17 (17p13.1)• TP53 gene encodes at least 15 protein
isoforms [1]• Actual molecular weight is 43.7 kda [2]
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P53 protein Structure
N-Terminus C-Terminus
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p53 helps in cell repair mechanism
p53 Gene
p53 Gene
Continues cell division
P53 Gene Stop’s the cell Division
Halt’s the cell
Cell Cycle
Heavy Damage
Minor Damage
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p53 Gene p53 Protein p53 protein binds to DNA
p21 Genep21 Protein
Stimulates p21 gene
p21 Protein blocks CDK-2
MOLECULAR APPROACH [3]
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Inhibition during Cell Division
CDK-2
p21 inhibits CDK-2
p53 P21 protein
Damage cell
APOPTOSIS
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RISE OF MUTATED p53 THROUGH BASE MUTATION/ POINT MUTATION
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INACTIVATION OF NORMAL p53 AND ACTIVATION OF MUTATED p53
N-TerminusC-Terminus
Point Mutation Acquires GOF
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RECRUITMENT MECHANISM TO THE PROMOTER
• To analyze GOF • mtp53 can be recruited to promoters via interaction with other
transcriptional factors acc. to [4,5,6,7,8]• Binding factors- E2F1, NF-Y, VDR, ETS1, ETS2, and SP1 also
binds with normal p53 acc. To [4,5,6,7,8,9]• Mtp53 gene expression with help MRD1 promoter and stated
ETS-1 can interact with mtp53 not with normal p53. ETS factor is require for transcriptional regulatory activity of mtp53. [10]
• Other studies revealed ETS1 also require to normal p53 gene for transcription regularities.
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DOMAIN REQUIREMENTS FOR MUTANT p53 TRANSCRIPTIONALLY DEPENDENT GOF [8,15]
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CONCLUSION
• ETS and mtp53 help each other for their profit.
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Reference• 1 Surget S, Khoury MP, Bourdon JC (19 December 2013). "Uncovering the role of p53 splice variants in human malignancy:
a clinical perspective". OncoTargets and Therapy 7: 57–68. doi:10.2147/OTT.S53876. PMID 24379683.• 2 Ziemer MA, Mason A, Carlson DM (1982). "Cell-free translations of proline-rich protein mRNAs". J. Biol. Chem. 257 (18):
11176–80. PMID 7107651.• 3 http://www.ncbi.nlm.nih.gov/• 4. Di Agostino S, Strano S, Emiliozzi V, Zerbini V, Mottolese M, Sacchi A, et al. Gain of function of mutant p53: the mutant
p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer Cell (2006) 10(3):191–202. doi:10.1016/j.ccr.2006.08.013
• 5. Fontemaggi G, Dell’Orso S, Trisciuoglio D, Shay T, Melucci E, Fazi F, et al. The execution of the transcriptional axis mutant p53, E2F1 and ID4 pro-motes tumor neo-angiogenesis. Nat Struct Mol Biol (2009) 16(10):1086–93. doi:10.1038/nsmb.1669
• 6. Stambolsky P, Tabach Y, Fontemaggi G, Weisz L, Maor-Aloni R, Siegfried Z, et al. Modulation of the vitamin D3 response by cancer-associated mutant p53. Cancer Cell (2010) 17(3):273–85. doi:10.1016/j.ccr.2009.11.025
• 7. Do PM, Varanasi L, Fan S, Li C, Kubacka I, Newman V, et al. Mutant p53 cooperates with ETS2 to promote etoposide resistance. Genes Dev (2012) 26(8):830–45. doi:10.1101/gad.181685.111
• 8. Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, et al. Gain- of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature (2015) 525(7568):206–11. doi:10.1038/nature15251
• 9. Borellini F, Glazer RI. Induction of Sp1-p53 DNA-binding heterocomplexes during granulocyte/macrophage colony-stimulating factor-dependent proliferation in human erythroleukemia cell line TF-1. J Biol Chem (1993) 268(11):7923–8.
• 10.Sampath J, Sun D, Kidd VJ, Grenet J, Gandhi A, Shapiro LH, et al. Mutant p53 cooperates with ETS and selectively up-regulates human MDR1 not MRP1. J Biol Chem (2001) 276(42):39359–67. doi:10.1074/jbc.M103429200
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Summary
• CANCER Introduction• Structure of p53• Function of p53• Literature Review• Conclusion
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Questionnaire
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