Powerful E3 Ligase Degrades Tumor Suppressor p53 During DNA Damage

ABSTRACT:

The ubiquitination pathway is dynamic and regulates degradation of many proteins. Additionally, p53 undergoes Mdm-2–mediated ubiquitination and proteasomal degradation. Loss of p53 in tumor cells enhances HIF-1 activity. Genetic alterations drive oncogenesis. Moreover, in mammalian cells, p53 protein is part of regulatory and signaling pathways that control cell fate. p53 binds to double-stranded DNA. Furthermore, the transcriptional activity of p53 supports senescence, cell cycle regulation, and DNA repair. p53 moves to the cytoplasm. In summary, p53 plays an essential role in human tumorigenesis.

KEYWORDS: ubiquitination, oncogenesis, control, transcriptional, regulation

INTRODUCTION

P53 and cellular control

The cell is a dynamic system with growth as a key feature. It increases in size and weight as it develops. Normal living cells are mortal and therefore die after a period. A normal cell would be transformed into a cancerous cell only through serious change.

Moreover, P53 was identified in 1979 by Lionel Crawford, David P. Lane, Arnold Levine and Lloyd old working at Imperial Cancer Research Fund (UK), Princeton University and Memorial Sloon Kettering Cancer Center, respectively. They worked at those institutions to uncover its role in safeguarding the genome.

Additionally, the tumor-suppressor protein exerts antiproliferative effects, helping limit cell growth. The activity is abrogated by mutations that occur frequently in tumors. Mdm2 is an oncoprotein and a potent inhibitor of p53. Mdm2 binds the domain of p53 and blocks its ability to regulate target genes, affecting apoptosis and cell cycle control. Protein degradation plays an important role in almost every basic cellular process, including cell cycle control, differentiation, DNA repair and regulation of the immune and inflammatory response. The tumor suppressor is a key substrate for the ubiquitin proteasome degradation pathway.

Degradation of p53:

Wild type p53 is a short lived protein that accumulates various types of stress. Degradation of p53 via the ubiquitin proteasome pathway. Ubiquitin is 76 based amino acid protein. Ubiquitin can be activated attached by ubiquitin-activating enzymes(E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s) mediated pathway respectively. The p53 is further polyubiquitinated either by p300 or Mdm2. Recently, two additional E3s ubiquitin ligases -Pihr2 and COP1 were demonstrated. Expression of COP1 inhibits p53 dependent transcription and p53 degradation has been observed in the absence of Mdm2.

 Functions of p53:

The functions of p53 tumor suppressor proteins involve precise interactions with other proteins and regulation of transcriptional activity.

p53 is a key regulator of cell cycle control.

The transcriptional activity of p53 governs senescence, apoptosis, DNA repair, tumorigenesis, and metabolism.

regulation. Particularly, the E3 ubiquitin ligases in p53 stability and functions can lead to development of new drugs that can improve patients survival rates.

CONCLUSION:

p53 gene is plays a central role in the protection our body from cancer. p53 is uniquely valuable target for basic as well as applied research.

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REFERENCES:

1.Nature 387, 296-299 (15 May 1997)

doi: 10.1038/387296a0

2.Biochim Biophys Acta. 1996 Jun 7;1287(2-3):77-102.

3.Curr Opin Cell Biol. 2001 Dec;13(6):738-47.

4.(2018). Primary information of p53 gene. Retrieved from last http://www.biojinformatics.org/p53/introduction.html.

5.Yosef Shaul, G. A. (2006). Ubiquitin-Independent Degradation: Lessons from the p53 Model. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel, 8, 1-4.

6.Wensheng Yang & Wafik S. El-Deiry (2007) CARPs are E3 ligases that target apical caspases and p53, Cancer Biology & Therapy, 6:11, 1676-1683, DOI: 10.4161/cbt.6.11.4939

7.www.pnas.orgcgidoi10.1073pnas.0905997106

8.Bing Zhoub, L. Y., & , e. a. (2015). RNF125 is a Ubiquitin-Protein Ligase that Promotes p53 Degradation . Cellular Physiology and Biochemistry Cellular Physiology, 237-245.

9.Khosrow Rezvani, S. S. (2017). Essential Roles of E3 Ubiquitin Ligases in p53 Regulation . International Journal of Molecular Sciences, 18.

10.DOI 10.1016/j.molecule.2006.01.020

11.FEBS Lett. 2011 September 16; 585(18): 2803–2809. doi:10.1016/j.febslet.2011.05.022.

12. Bijoyesh Mookerjee, R. R., & , Z. M. B. (1999). Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1a. Genes & Development, 34-45.

13.https://doi.org/10.1016/S0014-5793(97)01480-4