Navigation Links
Researchers discover second protective role for tumor-suppressor
Date:2/18/2010

HOUSTON - ATM, a protein that reacts to DNA damage by ordering repairs or the suicide of the defective cell, plays a similar, previously unknown role in response to oxidative damage outside of the nucleus, researchers report this week in the online version of the Proceedings of the National Academy of Sciences.

"This tumor-suppressor that works in the nucleus to prevent replication of defective cells also has a second life out in the cytoplasm, which was totally unexpected," said senior author Cheryl Walker, Ph.D., professor in The University of Texas M. D. Anderson Cancer Center Department of Carcinogenesis.

"ATM recognizes damage caused by reactive oxygen species (ROS) and tells the cell to stop growing by suppressing the protein-synthesizing pathway mTORC1 or orders the cell to consume itself, a process called autophagy," Walker said. This pathway parallels the protein's role of damage recognition and response in the nucleus.

Reactive oxygen species are a byproduct of cellular metabolism and in small amounts play a role in cell signaling. Their ability to react with other molecules makes them toxic, and they are kept in check by antioxidant enzymes. When that natural balance is disrupted, elevated levels of these volatile molecules damage proteins, lipids and DNA, Walker said.

The authors note that elevated ROS has been linked to more than 150 diseases, including diabetes, cancer, neurodegenerative diseases and atherosclerosis.

In its previously known role, ATM (short for Ataxia-Telangiectasia Mutated) senses DNA damage, orders the cell to repair the damage and halts cell division pending repair via the tumor suppressor p53. If repair is not possible, ATM sets off apoptosis - programmed cell death. ATM is commonly mutated in cancer.

The added protective role discovered by the researchers also points to a potential way to activate the tumor-suppressor without damaging DNA.

Walker's lab was studying another tumor-suppressing protein called TSC2 that is active in the cellular cytoplasm and found that ATM appeared to be associated with TSC2 activation.

In a series of experiments, the research team uncovered the molecular pathway that begins with ROS activation of ATM which then:

  • Activates the tumor suppressor LKB1, which in turn phosphorylates and activates the AMP kinase (AMPK), a key player in energy sensing and growth factor signaling.

  • AMPK switches on the tumor-suppressor TSC2 (tuberous sclerosis complex 2).

  • TSC2 then suppresses the kinase mTOR (mammalian Target of Rapamycin), which shuts down the mTORC1 signaling pathway, an important regulator of protein creation and cell growth.

  • Because TORC1 suppresses autophagy, when TORC1 is suppressed by TSC2, autophagy is free to occur.

During autophagy, membranes form around organelles in the cytoplasm, which are subsequently digested. Autophagy plays a normal role in cell growth and stability, and is a natural cellular defense mechanism, providing nutrients for a starving cell, for example.

Autophagy also is thought to be a second form of programmed cell death, because it can eventually kill the cell, cannibalizing it and leaving it shot full of cavities. Whether autophagy is activated as a survival mechanism in response to ROS or as an ATM-driven programmed cell death remains to be explored, the authors noted.

Even so, the study links oxidative stress to a key metabolic pathway activated by ATM that integrates damage response pathways with energy signaling, protein synthesis and cell survival.


'/>"/>

Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

Related medicine news :

1. Stanford researchers find culprit in aging muscles that heal poorly
2. UCLA researchers identify markers that may predict diabetes in still-healthy people
3. Mayo Clinic researchers discover new diagnostic test for detecting infection in prosthetic joints
4. Bipolar disorder relapses halved by Melbourne researchers
5. Cell that triggers symptoms in allergy attacks can also limit damage, Stanford researchers find
6. High and mighty: first common height gene identified by researchers behind obesity gene finding
7. Researchers estimate about 9 percent of US children age 8 to 15 meet criteria for having ADHD
8. Majority of 2.4 Million U.S. Children With ADHD Not Diagnosed or Consistently Treated, According to New Gold Standard Study by Cincinnati Childrens Researchers
9. Researchers develop long-lasting growth hormone
10. Jefferson immunology researchers halt lethal rabies infection in brain
11. Purdue researchers develop technology to detect cancer by scanning surface veins
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/5/2016)... ... February 05, 2016 , ... Freed-Hardeman University President Joe ... signed a joint enrollment and degree completion agreement. The agreement, which begins ... degrees at FHU|Dickson. , The agreement allows students to be jointly admitted ...
(Date:2/5/2016)... ... February 05, 2016 , ... In the fourth ... country gathered at the La Valencia Hotel in San Diego, California to discuss ... named the year’s most outstanding franchise, walking away with the coveted David Wright ...
(Date:2/5/2016)... SARASOTA, Fla., (PRWEB) , ... February 05, 2016 , ... ... appetizing recipes just in time for this weekend’s Big Game. Take the stress out ... ingredients that will keep your guests happy at every stage of the game. , ...
(Date:2/5/2016)... ... February 05, 2016 , ... Stuart Bentkover, MD, FACS is ... to provide the most effective tattoo removal today, Dr. Bentkover is the only doctor ... by Cynosure, the PicoSure has been approved by the Food and Drug Administration (FDA) ...
(Date:2/5/2016)... ... February 05, 2016 , ... Health and wellness is a topic that should ... event they are experiencing an illness. Migraines are a severe form of a headache ... migraines would not wish the pain on their worst enemy, the feeling can last ...
Breaking Medicine News(10 mins):
(Date:2/4/2016)... Calif. , Feb. 4, 2016  Edwards Lifesciences ... patient-focused innovations for structural heart disease and critical care ... accelerated share repurchase (ASR) agreement with Morgan Stanley & ... stock.  This repurchase is part of the Company,s previously ... the Company,s common stock.  --> ...
(Date:2/4/2016)... Feb. 4, 2016 Worldwide Radiology Oncology ... growth as next generation systems provide a way ... for cancer surgery. New systems pinpoint the delivery ... has been such a problem previously, limiting the ... robots take cancer surgery far beyond what has ...
(Date:2/4/2016)... Calif. , Feb. 4, 2016  SciClone ... today announced it has entered into a settlement ... Commission (SEC) fully resolving the SEC,s investigation into ... (FCPA).  Under the terms of the settlement agreement, ... $12.8 million, including disgorgement, pre-judgment interest and a ...
Breaking Medicine Technology: