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Researchers discover enzyme crucial to tumor development

Date:
December 7, 2016
Source:
American Technion Society
Summary:
Researchers have discovered a biological pathway that plays an important role in tumor development. The findings could lead to cancer-fighting drugs that work by shortening the half-life of select cancer-promoting proteins known as oncoproteins.
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An international team led by researchers from the Technion-Israel Institute of Technology's Rappaport Faculty of Medicine and the Technion Integrated Cancer Center (TICC) has discovered a biological pathway that plays an important role in tumor development. Published in Cell Reports, the findings could lead to cancer-fighting drugs that work by shortening the half-life of select cancer-promoting proteins known as oncoproteins.

As a rule, oncoproteins are short-lived, and play regulatory roles in "normal" (non-transformed) cells. But in cancer cells, they display enhanced stability, which gives cancer cells a longer life span. They also increase the aggressiveness of the cancer cells, which leads to tumor progression.

Led by Technion Associate Professor Amir Orian, the researchers found that RNF4 (a ubiquitin enzyme first detected in fruit flies, and later in human cancer cells) binds to these oncogenic proteins and provides them with a stabilizing structure. RNF4 itself is not an oncogenic protein, but oncogenic proteins and cancer cells are highly dependent on it.

"We have demonstrated that removing RNF4 leads to the death of the cancer cell, and hence the potential application of the discovery: the development of drugs that will inhibit the activity of RNF4 and significantly shorten the half-life of oncogenic proteins even in scenarios in which they are abnormally stabilized, thus indirectly eliminating the cancer cell," said Prof. Orian.

The researchers found an increased level of RNF4 in 30% of patients with colon cancer, and a link between that increase and reduced life expectancy in a group of breast cancer patients. Preliminary results from their lab also support the notion that RNF4 has essential roles in other types of cancer.

A twist in the ubiquitin system: from degradation and stabilization

One surprising twist to the team's findings is the role played by the ubiquitin system, which is best known as being responsible for the degradation of regulatory and damaged proteins. In this case, said Orian, it does the exact opposite -- it stabilizes the cancer proteins and prevents their degradation.

Prof. Orian, a graduate of the Technion Faculty of Medicine's MD/PhD program, studied the ubiquitin system as part of his doctoral work under Distinguished Professor Aaron Ciechanover. Prof. Ciechanover won the 2004 Nobel Prize in Chemistry, together with his Technion colleague Prof. Avram Hershko, and Prof. Irwin Rose from the University of California, for the discovery of the ubiquitin system.

This system, one of the most important and vital control systems in the body, attaches a "death tag" (ubiquitin) to regulatory proteins or damaged proteins. In many cases ubiquitin tagging targets these proteins for degradation with proteasome, a multi-protein complex that operates as a protein crusher. But in this case, RNF4 and the ubiquitin system generate a unique "stabilizing" tag.


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Materials provided by American Technion Society. Note: Content may be edited for style and length.


Journal Reference:

  1. Jane J. Thomas, Mona Abed, Julian Heuberger, Rostislav Novak, Yaniv Zohar, Angela P. Beltran Lopez, Julie S. Trausch-Azar, Ma. Xenia G. Ilagan, David Benhamou, Gunnar Dittmar, Raphael Kopan, Walter Birchmeier, Alan L. Schwartz, Amir Orian. RNF4-Dependent Oncogene Activation by Protein Stabilization. Cell Reports, 2016; 16 (12): 3388 DOI: 10.1016/j.celrep.2016.08.024

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American Technion Society. "Researchers discover enzyme crucial to tumor development." ScienceDaily. ScienceDaily, 7 December 2016. <www.sciencedaily.com/releases/2016/12/161207180712.htm>.
American Technion Society. (2016, December 7). Researchers discover enzyme crucial to tumor development. ScienceDaily. Retrieved May 27, 2017 from www.sciencedaily.com/releases/2016/12/161207180712.htm
American Technion Society. "Researchers discover enzyme crucial to tumor development." ScienceDaily. www.sciencedaily.com/releases/2016/12/161207180712.htm (accessed May 27, 2017).

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