Featured Research

from universities, journals, and other organizations

Towards medical treatments using cell level control

Date:
October 31, 2012
Source:
Tokyo Institute of Technology
Summary:
Researchers in Japan and Israel have identified a means of controlling biological processes that could help treatments for immune disease, neurological disorders and cancer.

Researchers at Tokyo Institute of Technology and the Weizmann Institute of Science identify a means of controlling biological processes that could help treatments for immune disease, neurological disorders and cancer.

The cellular response to a number of signals including inflammatory cytokines, tumor promoters, carcinogens, and chemotherapeutic agents hinge on the transcription factor NF-κB. Rivka Dikstein and colleagues at Tokyo Institute of Technology in Japan and the Weizmann Institute of Science in Israel identify how the protein DSIF controls NF-κB activity. The research may lead to methods for controlling inflammation, and immune responses, as well as the cell cycle processes that can lead to cancer.

Activity of NF-κB is usually transient because some of the gene products function as negative regulators of NF-κB, resulting in a negative feedback loop. This is desirable because persistent activation of NF-κB can lead to various pathogenic conditions such as chronic inflammation, autoimmune diseases, and cancer.

Dikstein and colleagues treated cells to reduce the expression of DSIF and monitored the effect on protein levels of NF-κB's target genes. They found that in the treated 'DSIF knockdown' cells the levels of these proteins failed to recover following a degradation process. Further investigation revealed that DSIF plays an integral role in the maturation and transport of messenger RNAs.

"The unique control of the negative feedback regulator genes by DSIF may be utilized by cells under circumstances in which prolonged NF-κB activity is needed," explain the authors. Their future studies will focus on DSIF under specific settings with a view to identifying drug targets for selective manipulation of NF-κB activity.

Background

NF-κB induces gene expression responsible for a number of biological processes including inflammation and cell survival. Its deregulation is linked to chronic inflammation and cancer but so far the mechanisms behind these processes have not been fully understood.

Nuclear transport is integral to NF-κB activity. In unstimulated cells it is retained inactive in the cytoplasm. Signals that trigger its activation result in its transport into the nucleus where it activates responsive genes, such as A20 and IκBα.

Activity of NF-κB is usually transient because products of these genes function as negative regulators of NF-κB, resulting in a negative feedback and limiting the duration of NF-κB activation. In certain diseases NF-κB activation becomes persistent, perhaps due to an interruption of this feedback loop.

NF-κB activation results in recruitment of the protein DSIF at the target genes A20 and IκBα. The researchers confirmed the role of DSIF in the negative feedback regulation of NF-κB activity by downregulating a protein subunit of DSIF and comparing the treated cells with controls. In untreated cells the levels of proteins for the target genes A20 and IκBα are high. Although the levels diminish significantly in 30 minutes following a process called TNF-α induction, which is caused by degradation of the proteins, within 2 hours the levels recover. In knockdown cells, however, the levels remained diminished 2 hours after TNF-α induction.

Further investigations using chromatin immunoprecipitation assays revealed abnormalities in the synthesis of A20 and IκBα proteins in the knock down cells. A significant portion of the A20 and IκBα mRNAs in the knockdown cells were uncapped and unspliced (Fig. 2).

The researchers also studied how export was affected in DSIF knockdown cells. Export of mature mRNAs from the nucleus to the cytoplasm is a highly regulated process incorporating quality assurance checks. The researchers prepared RNA from cytosolic and nuclear cell fractions for comparison. In knockdown cells following TNF-α induction, the nuclear fractions had much larger amounts of A20 and IκBα than the cytosolic fractions, suggesting accumulation in the nucleus.

The impact observed on the synthesis and export of A20 and IκBα in DSIF knockdown cells was striking. A20 and IκBα are also responsible for regulating other cell signalling processes and it is likely that the effects on associated signalling processes contribute to the overall impact of DSIF knockdown.

As the authors point out, diminished DSIF activity could contribute to pathological states in which NF-κB becomes constitutively active, such as inflammatory and autoimmune diseases, neurological disorders, and cancer. Further work on DSIF activity could help develop new approaches to treating these diseases.

Acknowledgments

These results were conducted as part of the JST's PRESTO project, "Epigenetic control and biological functions" (Research Supervisor: Dr. Tsunehiro Mukai, professor emeritus, Saga University).


Story Source:

The above story is based on materials provided by Tokyo Institute of Technology. Note: Materials may be edited for content and length.


Journal Reference:

  1. Gil Diamant, Liat Amir-Zilberstein, Yuki Yamaguchi, Hiroshi Handa, Rivka Dikstein. DSIF Restricts NF-κB Signaling by Coordinating Elongation with mRNA Processing of Negative Feedback Genes. Cell Reports, 2012; 2 (4): 722 DOI: 10.1016/j.celrep.2012.08.041

Cite This Page:

Tokyo Institute of Technology. "Towards medical treatments using cell level control." ScienceDaily. ScienceDaily, 31 October 2012. <www.sciencedaily.com/releases/2012/10/121031122633.htm>.
Tokyo Institute of Technology. (2012, October 31). Towards medical treatments using cell level control. ScienceDaily. Retrieved September 22, 2014 from www.sciencedaily.com/releases/2012/10/121031122633.htm
Tokyo Institute of Technology. "Towards medical treatments using cell level control." ScienceDaily. www.sciencedaily.com/releases/2012/10/121031122633.htm (accessed September 22, 2014).

Share This



More Health & Medicine News

Monday, September 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Global Ebola Aid Increasing But Critics Say It's Late

Global Ebola Aid Increasing But Critics Say It's Late

Newsy (Sep. 21, 2014) More than 100 tons of medical supplies were sent to West Africa on Saturday, but aid workers say the global response is still sluggish. Video provided by Newsy
Powered by NewsLook.com
Sierra Leone in Lockdown to Control Ebola

Sierra Leone in Lockdown to Control Ebola

AP (Sep. 21, 2014) Sierra Leone residents remained in lockdown on Saturday as part of a massive effort to confine millions of people to their homes in a bid to stem the biggest Ebola outbreak in history. (Sept. 20) Video provided by AP
Powered by NewsLook.com
Sierra Leone's Nationwide Ebola Curfew Underway

Sierra Leone's Nationwide Ebola Curfew Underway

Newsy (Sep. 20, 2014) Sierra Leone is locked down as aid workers and volunteers look for new cases of Ebola. Video provided by Newsy
Powered by NewsLook.com
Changes Found In Brain After One Dose Of Antidepressants

Changes Found In Brain After One Dose Of Antidepressants

Newsy (Sep. 19, 2014) A study suggest antidepressants can kick in much sooner than previously thought. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins