A protein known for turning on genes to help cells survive low-oxygen conditions also slows down the copying of new DNA strands, thus shutting down the growth of new cells, Johns Hopkins researchers report. Their discovery has wide-ranging implications, they say, given the importance of this copying — known as DNA replication — and new cell growth to many of the body's functions and in such diseases as cancer.
"We've long known that this protein, HIF-1á, can switch hundreds of genes on or off in response to low oxygen conditions," says Gregg Semenza, M.D., Ph.D., a molecular biologist who led the research team and has long studied the role of low-oxygen conditions in cancer, lung disease and heart disorders. "We've now learned that HIF-1á is even more versatile than we thought, as it can work directly to stop new cells from forming." A report on the discovery appears in the Feb. 12 issue of Science Signaling.
With his team, Semenza, who is the C. Michael Armstrong Professor of Medicine at the Johns Hopkins University School of Medicine's Institute for Cell Engineering and Institute for Genomic Medicine, discovered HIF-1á in the 1990s and has studied it ever since, pinpointing a multitude of genes in different types of cells that have their activity ramped up or down by the activated protein. These changes in so-called "gene expression" help cells survive when oxygen-rich blood flow to an area slows or stops temporarily; they also allow tumors to build new blood vessels to feed themselves.
To learn how HIF-1á's own activity is controlled, the team looked for proteins from human cells that would attach to HIF-1á. They found two, MCM3 and MCM7, that limited HIF-1á's activity, and were also part of the DNA replication machinery. Those results were reported in 2011.
In the new research, Semenza and his colleagues further probed HIF-1á's relationship to DNA replication by comparing cells in low-oxygen conditions to cells kept under normal conditions. They measured the amount of DNA replication complexes in the cells, as well as how active the complexes were. The cells kept in low-oxygen conditions, which had stopped dividing, had just as much of the DNA replication machinery as the normal dividing cells, the researchers found; the difference was that the machinery wasn't working. It turned out that in the nondividing cells, HIF-1á was binding to a protein that loads the DNA replication complex onto DNA strands, and preventing the complex from being activated.
"Our experiments answered the long-standing question of how, exactly, cells stop dividing in response to low oxygen," says Maimon Hubbi, Ph.D., a member of Semenza's team who is now working toward an M.D. degree. "It also shows us that the relationship between HIF-1á and the DNA replication complex is reciprocal — that is, each can shut the other down."
Other authors on the report are Kshitiz, Daniele M. Gilkes, Sergio Rey, Carmen C. Wong, Weibo Luo, Chi V. Dang and Andre Levchenko, all of the Johns Hopkins University School of Medicine, and Deok-Ho Kim of the University of Washington, Seattle.
The study was funded by the U.S. Public Health Service (contracts N01-HV28180 and HHS-N268201000032c), the National Heart, Lung, and Blood Institute (grant number T32-HL007525), the National Institute of General Medical Sciences (grant number T32-GM008752), the American Heart Association (predoctoral fellowship 10PRE4160120), the Susan G. Komen Foundation (postdoctoral fellowship KG111254), the Foundation for Advanced Research in the Medical Sciences and the Johns Hopkins Institute for Cell Engineering.
Link to the paper: http://stke.sciencemag.org/cgi/content/full/sigtrans;6/262/ra10
Shawna Williams | Newswise
The balancing act: An enzyme that links endocytosis to membrane recycling
07.12.2016 | National Centre for Biological Sciences
Transforming plant cells from generalists to specialists
07.12.2016 | Duke University
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
07.12.2016 | Health and Medicine
07.12.2016 | Life Sciences
07.12.2016 | Health and Medicine