Activity of p53 in Cancer Progression and metastasis

ByAshish Kumar

M.Tech 1st year

OUTLINE

• CANCER Introduction• Structure of p53• Function of p53• Literature Review• Conclusion• References • Summary • Questionnaire

Objective

• To give knowledge of cancer along with brief description of p53 gene

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

Cancer

• Single type of cell proliferate continuously becomes immortal further into a tumor.

• Two types of tumor– Benign Tumor– Malignant Tumor

Who controls cancer in our body?

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]

P53 protein Structure

N-Terminus C-Terminus

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

p53 Gene p53 Protein p53 protein binds to DNA

p21 Genep21 Protein

Stimulates p21 gene

p21 Protein blocks CDK-2

MOLECULAR APPROACH [3]

Inhibition during Cell Division

CDK-2

p21 inhibits CDK-2

p53 P21 protein

Damage cell

APOPTOSIS

RISE OF MUTATED p53 THROUGH BASE MUTATION/ POINT MUTATION

INACTIVATION OF NORMAL p53 AND ACTIVATION OF MUTATED p53

N-TerminusC-Terminus

Point Mutation Acquires GOF

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.

DOMAIN REQUIREMENTS FOR MUTANT p53 TRANSCRIPTIONALLY DEPENDENT GOF [8,15]

CONCLUSION

• ETS and mtp53 help each other for their profit.

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

Summary

• CANCER Introduction• Structure of p53• Function of p53• Literature Review• Conclusion

Questionnaire

Ashish Kumar

ashish.narayan.ashu@gmail.com

9555564734