Navigation Links
Scripps Research Institute scientists reveal molecular 'yin-yang' of blood vessel growth
Date:6/18/2014

LA JOLLA, CAJune 18, 2014 Biologists at The Scripps Research Institute (TSRI) have discovered a crucial process that regulates the development of blood vessels. The finding could lead to new treatments for disorders involving abnormal blood vessel growth, including common disorders such as diabetic retinopathy and cancer.

"Essentially we've shown how the protein SerRS acts as a brake on new blood vessel growth and pairs with the growth-promoting transcription factor c-Myc to bring about proper vascular development," said TSRI Professor Xiang-Lei Yang. "They act as the yin and yang of transcriptional regulation."

Yang and her colleagues reported the new findings this week in the biology journal eLife.

Multitasking Enzymes

SerRS (seryl tRNA synthetase) belongs to a family of enzymes that have fundamental, evolutionarily ancient roles in the protein-making machinery of cells. But as Yang's and other laboratories have been finding in recent years, some of these protein-maker enzymes seem to have evolved extra functions.

SerRS in particular has taken on a second basic role in animal biology. Findings from other laboratories in 2004 and 2009, mainly from genetic studies of zebrafish, first pointed to its involvement in vascular development, also known as angiogenesis. Animals with mutations to a certain part of the SerRS gene developed abnormal blood vessel systems, accompanied by excess levels of the key blood-vessel growth factor VEGFA. The implication was that SerRS somehow is needed for the proper regulation of VEGFA.

In a report published in 2012, Yang and her laboratory analyzed the portion of the SerRS protein that appears to mediate its involvement in vascular development. They found that this part of SerRS contains a special molecular homing sequence, apparently acquired several hundred million years ago during the emergence of vertebrates. The homing sequence causes a significant fraction of SerRS proteins to be transported away from the protein-making machinery of the cytoplasm and into the cell nucleus, where SerRS performs its angiogenesis-regulating function. "In that work we were able to show that SerRS's regulation of vascular development depends on the presence of this nuclear localization sequence," Yang said.

What remained to be determined was just how SerRS proteins in the nucleus regulate VEGFA. In the new study, she and her team set out to answer that question.

A Delicate Balance of Power

The scientists, including lead author Yi Shi, a staff scientist in the Yang Laboratory, started by confirming that a knockdown of nucleus-homing SerRS in human cells leads to a big jump in VEGFA productionconsistent with nuclear SerRS's apparent role in suppressing VEGFA.

Shi, Yang and their colleagues then determined that SerRS binds to a "promoter region" of DNA near the VEGFA genein fact, to the same site where the transcription factor protein c-Myc, a known driver of new vessel growth, normally binds. The scientists were able to show that SerRS essentially competes with c-Myc for binding to this promoter region.

However, they found that SerRS does more than just elbow c-Myc aside. Whereas c-Myc promotes VEGFA transcription by adding acetyl groups to the local DNA structure, opening it up and making the gene easier to reach with transcription enzymes, SerRS has the opposite effect: It gets rid of those acetyl groups so that the local DNA closes up again. In this way more than any other, SerRS suppresses the VEGFA gene transcription that c-Myc enables.

A key finding here was that SerRS achieves this deacetylation of VEGFA DNA by recruiting a partner, the deacetylase enzyme SIRT2which had never before been linked to angiogenesis. To confirm SIRT2's role, they knocked it down in zebrafish and found virtually the same vessel overgrowth that is seen when SerRS's nuclear-homing sequence is missing.

"Clearly the balance of influences between SerRS and c-Myc on VEGFA is important for vascular development," said Shi.

Antitumor Strategies

The new findings may end up being most relevant to antitumor strategies. SIRT2 was already considered a tumor suppressor, and c-Myc has long been known as a tumor-promoting "oncogene." A strong suggestion of this study is that SerRS, as the partner of SIRT2 in thwarting c-Myc's angiogenesis activity, may be a tumor suppressor with untapped therapeutic potential.

It may also work in that role more broadly than has been shown so far. "It has been estimated that c-Myc regulates 15 percent of human genes, so it's important to know where else SerRS opposes its activity," said Yang. "That's a clear direction for further research."


'/>"/>

Contact: Madeline McCurry-Schmidt
madms@scripps.edu
858-784-9254
Scripps Research Institute
Source:Eurekalert  

Related biology news :

1. Scripps Research discoveries lead to newly approved drug for infant respiratory distress syndrome
2. Scripps Research Institute scientists find promising vaccine targets on hepatitis C virus
3. Scripps Research Institute Professor Gerald F. Joyce elected to American Academy of Arts & Sciences
4. Scripps Research Institute scientists develop antidote for cocaine overdose
5. Scientist wins $3 million renewal of one of longest-running NIH grants to Scripps Research
6. Scripps research scientists find anticonvulsant drug helps marijuana smokers kick the habit
7. Scripps Florida scientist awarded $1.5 million to design therapeutics with new RNA approach
8. Scripps Florida scientists identify neurotranmitters that lead to forgetting
9. Plastic trash altering ocean habitats, Scripps study shows
10. Scripps Florida scientists awarded $8.4 million grant to develop new anti-smoking treatments
11. Esther B. OKeeffe Foundation gives $2 million to the Scripps Research Institute
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Scripps Research Institute scientists reveal molecular 'yin-yang' of blood vessel growth
(Date:3/27/2017)... , March 27, 2017  Catholic Health ... and Management Systems Society (HIMSS) Analytics for achieving ... Adoption Model sm . In addition, CHS previously ... U.S. hospitals using an electronic medical record (EMR). ... its high level of EMR usage in an ...
(Date:3/24/2017)... DUBLIN , Mar 24, 2017 Research ... Vehicle Access System Market Analysis & Trends - Industry Forecast to ... ... poised to grow at a CAGR of around 15.1% over the ... This industry report analyzes the market estimates and forecasts for ...
(Date:3/23/2017)... 2017 Research and Markets has announced the ... Trends - Industry Forecast to 2025" report to their offering. ... The Global ... of around 8.8% over the next decade to reach approximately $14.21 ... market estimates and forecasts for all the given segments on global ...
Breaking Biology News(10 mins):
(Date:10/11/2017)... ... 2017 , ... Personal eye wash is a basic first aid supply for any work environment, ... eye do you rinse first if a dangerous substance enters both eyes? It’s one less ... with its unique dual eye piece. , “Whether its dirt and debris, or an acid ...
(Date:10/11/2017)... ... , ... Disappearing forests and increased emissions are the main causes of the ... Especially those living in larger cities are affected by air pollution related diseases. , ... pollution-affected countries globally - decided to take action. , “I knew I had to ...
(Date:10/10/2017)... , ... October 10, 2017 , ... ... Center’s FirstHand program has won a US2020 STEM Mentoring Award. Representatives of the ... for Excellence in Volunteer Experience from US2020. , US2020’s mission is to change ...
(Date:10/10/2017)... ... 2017 , ... The Pittcon Program Committee is pleased to ... who have made outstanding contributions to analytical chemistry and applied spectroscopy. Each award ... conference and exposition for laboratory science, which will be held February 26-March 1, ...
Breaking Biology Technology: