MDM2 and p53 Signaling in Cancer

Paper Summary:

The paper analyzes the article "Small-Molecule MDM2 Antagonists Reveal Aberrant p53 Signaling in Cancer: Implications for Therapy" and explains the conclusions reached by the authors. The paper is of the opinion that the conclusions may have been slightly optimistic. The paper outlines the method used by the study discussed in the article and notes several limitations of the study.

Outline:
Summary
Method

From the Paper:

"The main focus of the article is around the protein murine double minute 2 (MDM2). MDM2 is a negative regulator of the p53 tumour suppressor protein. This is done through three mechanisms. Firstly, MDM2 binds at the p53 transactivation site and blocks its activation of transcription initiation [1]. Secondly, it participates in the nuclear export of p53 [1]. Thirdly, it serves as a ubiquitin ligase, promoting the degradation of p53. When p53 is activated, it can bring a halt upon the cell cycle and cause apoptosis [1]. This is very important as p53 acts as a transcription factor, the inactivation of which halts cellular apoptosis. In approximately half of all tumours that are malignant, p53 is perminantly disabled or deleted. However, in the other 50% of mutated cells, p53 simply remains inactive the misexpression of MDM2, which interferes with the proper functions of p53 [1]. So the object of the article is that disruption or inhibition of the MDM2-p53 interaction may correct p53 functioning and serve as a form of cancer therapy, such as suppression of tumour growth. Subsequently the problem that the authors tackle with is how to inhibit the actions of MDM2."

Sample of Sources Used:

• Christian Tovar, James Rosinski, Zoran Filipovic, Brian Higgins, Kenneth Kolinsky, Holly Hilton, Xiaolan Zhao, Binh T. Vu, Weiguo Qing, Kathryn Packman, Ola Myklebost, David C. Heimbrook and Lyubomir T. Vassilev. 2006. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: Implications for therapy. PNAS, 103(6): 1888-1893.
• Lyubomir T. Vassilev, Binh T. Vu, Bradford Graves, Daisy Carvajal, Frank Podlaski, Zoran Filipovic, Norman Kong, Ursula Kammlott, Christine Lukacs, Christian Klein, Nader Fotouhi, and Emily A. Liu. 2004. In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2. Science Express. Vol. 303. no. 5659, p844 - 848.
• Lyubomir T. Vassilev. 2006. MDM2 inhibitors for cancer therapy. TRENDS in Molecular Medicine, 13(1): 23-31.

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