Researchers at the University of Texas M. D. Anderson Cancer Center have found a protein that enables cellular survival during periods of low oxygen, or hypoxia, which also is key for development of many kinds of cancer.
In the Nov. 2 issue of Cell, they report that this protein, known as SENP1 (Sentrin/SUMO-specific protease 1), might provide a basis for future targeted therapies. They have already started to develop an agent to stop SENP1 from working in cells, which could push a tumor to stop growing and to wither away.
"We believe this emerging pathway of biological regulation plays an important role in cancer development," says the study's lead author, Edward T. H. Yeh, M.D., professor and chair of the Department of Cardiology at M. D. Anderson Cancer Center.
"We had found earlier that high levels of SENP1 can be found in prostate cancer, but we didn't understand why," Yeh says. "Now, knowing that it regulates the entire hypoxic response, we believe it must play a role in other kinds of cancers."
Researchers believe tumors adapt to low oxygen levels caused by their own rapid growth by turning on molecules that help tumors build a new blood supply. Yeh and colleagues found that SENP1 is needed for that process and that inhibiting it might be one way to turn off tumor growth.
The work described in Cell is a continuation of a series of discoveries in the Yeh lab. The scientists discovered what they dubbed Sentrin and later named SUMO (Small Ubiquitin-related Modifier) proteins. Like their 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. 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 1,000 proteins, many of which are transcription factors - proteins in the cell nucleus that bind to DNA to help transcribe genetic information.
Yeh discovered SENP1, which snips SUMO off proteins. This dynamic process is called SUMOylation and deSUMOylation, 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. In this paper, Yeh, and three 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 day 13 to 15 of the 21 day gestational period. "We 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."
They 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 factor1" (HIF1") become active.