Paper of the Month: Non-canonical suppression of p53 ubiquitination by Otubain1
This month's featured paper is from the Mushui Dai lab, and is titled, Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1. It was published in EMBO J. The research in this paper was conducted by scientists in the Department of Molecular & Medical Genetics*
p53 is the most frequently altered gene in human cancers. More than half of human cancers harbor mutations in the p53 gene and in the remaining cancers, p53 is often inactivated by defects in the p53 regulatory network.
“It seems almost impossible for a normal cell to become a cancer cell unless it inactivates the p53 network,” said Mushui Dai, MD, PhD, Assistant Professor, Department of Molecular & Medical Genetics. “Therefore, understanding the regulation of the p53 network, as well targeting the network, is pivotal for the development of cancer therapy.”
Previous studies have shown that in unstressed cells, p53 is kept at low levels through continuous degradation. This is primarily accomplished by an oncoprotein called MDM2. MDM2 is an enzyme (ubiquitin ligase also called E3) that can covalently attach p53 with ubiquitin molecules, a process called ubiquitination, and thus mark p53 for degradation.
In response to stress, p53 is rapidly stabilized in cells to induce cell growth arrest or apoptosis. This is achieved mainly through the interference with ubiquitination of p53 mediated by MDM2. Interestingly, ubiqutination of p53 is reversible. The enzymes responsible for this reverse process are called deubiquitinating enzymes, and several of these have been shown to cleave ubiquitin molecules off p53, protecting it from degradation.
An investigation in the Mushui Dai lab recently discovered the deubiquitinating enzyme Otubain 1 as a novel positive p53 regulator. Otubain1 stabilizes p53 and induces apoptosis and cell growth inhibition in cancer cells. Importantly, Otubain 1 is required for full activation of p53 in response to DNA damage.
“Because of this positive regulation, Otub1 might be a novel tumor suppressor in cells,” said Dr. Dai. “Interestingly, we have found that the expression of Otub1 is significantly reduced in about two-third of breast cancers. We will further investigate whether Otub1 is mutated or deregulated in other types of cancers.”
As a result of this investigation, Dr. Dai says he’s intrigued about how “Otubain 1 regulates p53 independently of its enzymatic activity to remove ubiquitin from p53.” He points out that it does so by using a novel non-canonical mechanism: binding to and suppressing the activity of another enzyme, UbcH5 (ubiquitin-conjugating enzyme, also called E2) working on the upstream MDM2-mediated p53 ubiquitination.
“Initially, we reasoned that if the enzymatic activity were required, mutating the catalytic site would abolish Otubain 1’s function to stabilize p53,” said Dr. Dai. “This has not been the case. Then we started looking into other mechanisms of action and discovered this novel non-canonical mechanism.”
Looking forward, a number of important questions arise from Dr. Dai’s study. Among them, Dr. Dai said, “It will be of great interest to know how Otubain 1 interferes with UncH5 function. Although we currently don’t know the answer, our finding has translational significance. For example, we can screen small molecule inhibitors to target UbcH5 for cancer therapy. Such inhibitors would work best on tumors that contain wild-type p53. This might be a new way to target the p53 network for future cancer therapy.”
Pictured above (Left to right): Mushui Dai, MD, PhD; Xiaoxin Sun, MD, PhD; Tiffany DeVine; Huiyan Chen, MD; Kishore B. Challagundla, PhD.
Mushui Dai, MD, PhD; Xiaoxin Sun, MD, PhD; Kishore B. Challagundla, PhD
Department of Molecular & Medical Genetics, School of Medicine, OHSU Knight Cancer Institute
ABOUT THE PAPER OF THE MONTH
The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, PhD.
In this paper, the findings by Dr. Dai's team reveal a surprise role for Otubain1, a deubiquitinating enzyme, in the regulation of p53 that have led to a new understanding of how p53 controls cell proliferation. This unexpected result may yield new strategies for the control of the p53 regulatory network in the setting of cancer and uncontrolled cell growth.