Yeh Discovers Links Connecting Oxygen, Cancer and Heart Diseases

Edward T.H. Yeh, M.D., director of the Center for Cardiovascular Diseases at The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM) has published findings on how hypoxia, or low oxygen, regulates the development of cancer and heart disease through a special protein that his laboratory discovered several years ago.

Edward T.H. Yeh, M.D.

In the November 2, 2007, issue of Cell, Yeh reported that this protein, known as SENP1 (Sentrin/SUMO-specific protease 1), might provide a basis for cancer and heart disease treatments. "We believe this emerging pathway of biological regulation plays an important role in cancer development and heart disease," said Yeh, the study's lead author.

The work described in Cell is a continuation of a series of discoveries in the Yeh lab. His laboratory was first to find what they dubbed Sentrin and later named SUMO (Small Ubiquitin-related Modifier) proteins in 1996. This discovery was one of the first papers published from the IMM. "Like the SUMO name suggests, these are mighty biological regulators that attach to other proteins in cells to modify their function or to move their location within a cell," Yeh explained. "Because they attach to many proteins and alter them, they resemble the well-known ubiquitin proteins which, by linking to proteins, target them for eventual break-down."

So far, SUMO has been found to alter the function of more than 2,000 proteins, many of which are transcription factors - proteins in the cell nucleus that bind to DNA to help transcribe genetic information. They also can be proteins that are involved in transmitting signals from the outside of the cell into the nucleus, a cell's information center. Thus, SUMO modification is now recognized as a major discovery in biology of the last decade.

Yeh also discovered that the process of adding SUMO to proteins is reversible, and in 2000, he found SENP1, which snips SUMO off proteins. This dynamic process is called SUMOylation and de- SUMOylation, and so far six different SENP family proteins have been found.

Although SENPs can reverse SUMOylation in many cases, their physiological role has not been well defined. Yeh and his colleagues sought to understand the role that SENP1 plays in normal development.

They bred mice to have a single copy of the SENP1 gene, instead of the normal two, and then they bred these mice again. Some of the offspring did not inherit any SENP1, and they all died between days 13 to 15 of the 21-day gestational period. "We looked for a reason that the mice would die on that period, and found that they had a problem making red blood cells," Yeh says. "They could only make about one fourth of the blood cells they needed, and that wasn't enough to sustain life."

Yeh looked at why the blood cells were deficient, and found that at that critical stage, blood cells required erythropoietin (EPO), a hormone that regulates blood cell maturation. "If you don't have EPO, red blood cells will die because they cannot mature," he says. That led to their first discovery - that SENP1 regulates EPO.

Regulation of EPO depends on the blood's oxygen level, and in hypoxic conditions, which occurs at that stage of development, transcription factors known as hypoxia inducible factor1a (HIF1a) become active.

"These proteins enter the cell nucleus to turn on transcription of the EPO gene," Yeh says. So they added another piece to the puzzle: SENP1 controls EPO production by regulating the stability of HIF1a. "When there isn't any SENP1, HIF1a is very unstable," he says. "It is not detectable in the embryo, compared to an embryo that has the SNEP1 gene."

Furthermore, he also discovered that proteins like vascular endothelial growth factor that build more blood vessels to seek new sources of oxygen also are deficient when SENP1 is absent. Thus, SENP1 is a master switch controlling the response to hypoxia, a condition common to the development of cancer and heart diseases. One can block the activity of SENP1 to decrease unwanted blood vessel formation in cancer or one can increase SENP1 activity to boost blood vessel development to treat heart disease.

"The discovery of SUMO is one of the most important discoveries made by The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases," said James T. Willerson, M.D., president of the health science center.

Yeh has two patents awarded in this field. He is considered the world leader in the study of ubiquitin and ubiquitin-like proteins. Since 2002, he organized four international conferences on ubiquitin, ubiquitin- like proteins, and cancer.

Yeh's laboratory also is at the forefront in deciphering the role of inflammation in the development of atherosclerosis and in the study of using stem cells to repair damaged heart muscles. He has written more than 100 scientific papers, many of which are landmark contribution to science and medicine. Since 1996, he has published 55 papers with attribution to the IMM.

Among his many honors, Yeh was elected to memberships in Academia Sinica, the Association of American Physicians, and the American Society for Clinical Investigation. He was selected as the Distinguished Alumnus of the University of California, Davis Medical School, and has served for 10 years as associate editor of Circulation. He is the past President of the Houston Cardiology Society and President of the board of the American Heart Association, Houston Chapter, and is currently a board member of the American Heart Association, South Central Affiliate, that covers Texas, Arkansas, Oklahoma, and New Mexico.

In addition to his affiliation with the IMM, Yeh founded the Department of Cardiology at The University of Texas M. D. Anderson Cancer Center in 2000. He also is on the faculty at the UT Graduate School of Biomedical Sciences.

With the continuing growth of the Department of Cardiology, Yeh has decided to leave the IMM and focus his efforts at M. D. Anderson Cancer Center. He will continue to collaborate with Dr. Willerson at the Texas Heart Institute (THI) "to build a world class stem cell center devoted to the cure of heart diseases."

Willerson originally recruited Yeh to Houston in the early 1990s, during the period when Willerson was first organizing the IMM, which consisted of a handful of researchers working in leased space.

"It was really exciting to see the IMM start with just a few people and watch it grow," Yeh recalled. "Dr. Willerson has certainly made the IMM possible. I think all of us who have been associated with the IMM are very proud of his vision."