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Constitutive Photomorphogensis Protein1 (COP1) mediated p53 pathway and its oncogenic role

Md. Golam Rabbani, Sk Amir Hossain, Khandker Khaldun Islam, Sarder Nasir Uddin.

We have reviewed the COP1 mediated tumor suppressor protein p53 pathway and its oncogenic role. COP1 is a negative regulator of p53 and acts as a pivotal controller of p53-Akt death-live switch (Protein kinase B). In presence of p53, COP1 is overexpressed in breast, ovarian, gastric cancers, even without MDM2 (Mouse double minute-2) amplification. Following DNA damage, COP1 is phosphorylated instantly by ATM (Ataxia telangiectasia mutated) and degraded by 14-3-3σ following nuclear export and enhancing ubiquitination. In ATM lacking cell, other kinases, i.e. ATR (ataxia telangiectasia and Rad3-related protein), Jun kinases and DNA-PK (DNA-dependent protein kinase) cause COP1 & CSN3 (COP9 signalosome complex subunit-3) phosphorylation and initiate COP1s down regulation. Although, it has been previously found that co-knockout of MDM2 and COP1 enhance p53s half life by eight fold, the reason is still unknown. Additionally, while interacting with p53, COP1 upregulate MDM2s E3 ubiquitin ligase, Akt, CSN6 (COP9 signalosome 6) activity and inhibit 14-3-3σs negative regulation on MDM2 and COP1 itself. Conclusively, there persists an amplification loop among COP1, MDM2, Akt and 14-3-3σ to regulate p53s stability and activity. However, the role of another tumor suppressor PTEN (phosphatase and tensin homologue) is yet to be discovered. This study provides insight on the molecular genetic pathways related to cancer and might be helpful for therapeutic inventions.

Key words: COP1; p53; 14-3-3σ; PTEN; MDM2; ATM; Akt; CSN3; CSN6; MLF1

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