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Suraj Prakash Sharma | Ekta Chotia


6.3.2.     p53

The p53 tumor suppressor gene is activated in response to a wide variety of cellular stresses including DNA damage, ribonucleotide depletion, redox modulation, hypoxia, changes in cell adhesion, and the stresses created by activated oncogenes. The p53 protein work as transcription factors and activated the genes which is involved in DNA repair, apoptosis and growth arrest. These activities of P53 help in maintaining the genomic stability. Hence P53 is called as guardian of genome.

If normal p53 is mutated and non-functional by binding of other protens.p53 has four functional domains involved transcription activation domain(TAD), DNA binding domain(DBD), oligomerization domain(OD), autoinhibitory domain(AID). Each domains binds to several proteins that regulate p53 function. P53 binds to its response element present upstream to the gene to transcribe the gene. P53 binds in tetrameric form. p53 increase the expression of Bax, p21, insulin-like growth factor binding protein 3(IGFB3), GADD45 and thrombospondin. Expression of genes such as Bcl2, Fos and jun can be inhibited by p53. Thus p53 inhibits cell proliferation.

 The gene p21 that code for cyclin-dependent kinase inhibitor. p21 inactivates CDK that is essential for DNA synthesis. GADD  binds to a protein proliferating cell nuclear antigen(PCNA) that needed for both DNA synthesis and repair. Hence, p53 inhibit DNA synthesis while allowing repair to continue. DNA damage activates p53  function by post –transcriptional and cell-type specific mechanisms.

Normal p53 show inactivation by protein binding. For example- Adenovirus codes for E18 that binds to TAD of normal p53 and block its transcription. Some human sarcomas have mdm2 gene that have same end results. Human papilloma virus  have protein E6 that binds to OD and prevents dimerisation, while the HBX protein of hepatitis B virus binds and inactivates p53.

P53 transcribe the thrombospondin, PAI, KAI, BAI and they block the angiogenesis. Mutation in p53 thrombospondin, PAI, KAI, BAI.

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