Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Rare developmental disorder linked to tumor-suppressing protein, Stanford researchers find

04.08.2014

CHARGE, which affects 1 in 10,000 babies, is an acronym whose letters stand for some of the more common symptoms of the condition: coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness.

Originally, the researchers were examining the tumor-suppressive properties of the protein, called p53, not investigating developmental disorders. But when a mouse model developed a strange set of deficiencies, the researchers followed a trail of clues that led them to link p53 with CHARGE syndrome.

"It was a very big surprise and very intriguing," said Jeanine Van Nostrand, PhD, lead author of a paper describing the research and a former Stanford graduate student, now at The Salk Institute for Biological Studies. "P53 had never before been shown to have a role in CHARGE."

The paper will be published online Aug. 3 in Nature. The senior author is Laura Attardi, PhD, professor of radiation oncology and of genetics.

Cellular quality control regulator

The researchers originally created a mouse model that expressed a mutated form of the protein, known as p53, to investigate the behavior of p53 in suppressing tumors. Mice expressing only the mutated protein survived. But to their surprise, heterozygous mice, or those with one copy of the mutated p53 and one normal copy, developed symptoms of CHARGE and died in utero.

P53 is a cellular quality-control regulator. When it spots an ailing cell, it triggers other proteins to kill the cell or arrest its division. In a developing human or mouse, other proteins switch off p53 so it doesn't inadvertently kill important cells. The mutated form of p53 created by the researchers had a disabled off-switch, but it also couldn't communicate with other proteins to spark the cellular death. Therefore, a mouse containing only the mutated p53 survived to adulthood.

But when mice had one copy of a mutated p53 gene and one normal copy, the resultant proteins formed hybrids. These hybrid p53 proteins couldn't be turned off, but they retained the ability to trigger cellular death. Interestingly, these proteins only affected certain types of cells, causing the symptoms of CHARGE. The results suggest that p53 may play a role in other developmental disorders, Attardi said.

"It really reiterates how carefully p53 must be regulated," Attardi said. "It needs to be turned on at the right time and place. If it's not, it can cause damage."

CHARGE linked to gene mutation

The mechanisms of CHARGE syndrome remain a mystery, although it has been linked to a mutation in a gene called CHD7. Attardi's team examined the connection between p53 and CHD7. They discovered that the CHD7 protein can keep p53 turned off.

By linking p53 with CHARGE, this study elucidates molecular pathways that could be used to develop CHARGE therapies, said co-author Donna Martin, MD, PhD, associate professor of pediatrics and of human genetics at the University of Michigan Medical School and an expert on CHARGE.

###

Additional Stanford authors are former graduate students Colleen Brady, PhD, and Thomas Johnson, MD; postdoctoral scholar Heiyoun Jung, PhD; graduate students Daniel Fuentes, Chieh-Yu Lin and Chien-Jung Lin; Margaret Kozak, a former research assistant; Hannes Vogel, MD, professor of pathology and of pediatrics; Jonathan Bernstein, MD, assistant professor of pediatrics; and Joanna Wysocka, PhD, associate professor of chemical and systems biology and of developmental biology.

Other authors of the study are affiliated with Hôpital Necker-Enfants Malades in Paris, Université Paris Descartes, the Indiana University School of Medicine and the University of Michigan Medical School.

The study was supported by the National Science Foundation; the National Cancer Institute (grant 1F31CA167917); the National Institutes of Health (grants R01GM095555, R01DC009410, HL118087, HL121197 and R01CA140875); the American Heart Association; the March of Dimes Foundation; the American Cancer Society; and the Leukemia & Lymphoma Society.

Information about the Stanford's Department of Radiation Oncology and the Department of Genetics, which also supported the study, is available at http://radonc.stanford.edu and http://genetics.stanford.edu.

The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital Stanford. For information about all three, please visit http://stanfordmedicine.org/about/news.html.

Print media contact: Rosanne Spector at (650) 725-5374 (manishma@stanford.edu)

Broadcast media contact: M.A. Malone at (650) 723-6912 (mamalone@stanford.edu)

Rosanne Spector | Eurek Alert!

Further reports about: CHARGE Syndrome CHD7 Cancer Medicine death disorder heart defects p53 proteins symptoms

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>