Compound stimulates tumor-fighting protein in cancer therapy

Feb. 6, 2013 ? A compound that stimulates the production of a tumor-fighting protein may improve the usefulness of the protein in cancer therapy, according to a team of researchers, including several from the Penn State Hershey Cancer Institute and College of Medicine.

TRAIL is a natural anti-tumor protein that suppresses tumor development during immune surveillance -- the immune system's process of patrolling the body for cancer cells. This process is lost during cancer progression, which leads to uncontrolled growth and spread of tumors.

The ability of TRAIL to initiate cell death selectively in cancer cells has led to ongoing clinical trials with artificially created TRAIL or antibody proteins that mimic its action. Use of the TRAIL protein as a drug has shown that it is safe, but there have been some issues, including stability of the protein, cost of the drug, and the ability of the drug to distribute throughout the body and get into tumors, especially in the brain.

"The TRAIL pathway is a powerful way to suppress tumors but current approaches have limitations that we have been trying to overcome to unleash an effective and selective cancer therapy," said Wafik El-Deiry, professor of medicine and chief of the hematology/oncology division, Penn State College of Medicine. "The TRAIL biochemical cell death pathway naturally lends itself as a drug target to restore anti-tumor immunity."

Researchers have identified a compound called TRAIL-inducing Compound 10 (TIC10) as a potential solution. TIC10 stimulates the tumor suppression capabilities of TRAIL in both normal and tumor tissues, including in the brain, and induces tumor cell death in mice. They report their findings in the journal Science Translational Medicine.

TIC10 is a small molecule. This organic compound binds to a protein and alters what the protein does.

Stimulation of TRAIL protein is sustained in both tumor and normal cells, with the normal cells contributing to the TIC10-induced cancer cell death through a bystander effect. It is effective in cancer cell samples and cell lines resistant to conventional therapies.

"I was surprised and impressed that we were able to do this," El-Deiry said. "Using a small molecule to significantly boost and overcome limitations of the TRAIL pathway appears to be a promising way to address difficult to treat cancers using a safe mechanism already used in those with a normal effective immune system. This candidate new drug, a first-in-its-class, shows activity against a broad range of tumor types in mice and appears safe at this stage."

New treatments are needed for advanced cancer, as more than half a million people in the United States will die of cancer in 2013.

"We have enough preclinical information to support the rationale for testing this new drug in the clinic," El-Deiry said.

TIC10 seems to be nontoxic to normal cells or mice even at doses 10 times higher that an observed therapeutic dose. However, more research needs to be completed to satisfy FDA requirements prior to initiation of clinical testing.

Other researchers are Joshua E. Allen, David T. Dicker, Akshal S. Patel, Nathan G. Dolloff, Kimberly A. Scata,Wenge Wang, all of Penn State Hershey Cancer Institute; Gabriel Krigsfeld, Patrick A. Mayes, Luv Patel, University of Pennsylvania School of Medicine; Evangelos Messaris, Department of Surgery, Penn State College Medicine; Jun-Ying Zhou and Gen Sheng Wu, Wayne State University School of Medicine.

This study was funded by the American Cancer Society, Penn State Hershey Cancer Institute and the National Institutes of Health.

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The above story is reprinted from materials provided by Penn State.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. J. E. Allen, G. Krigsfeld, P. A. Mayes, L. Patel, D. T. Dicker, A. S. Patel, N. G. Dolloff, E. Messaris, K. A. Scata, W. Wang, J.-Y. Zhou, G. S. Wu, W. S. El-Deiry. Dual Inactivation of Akt and ERK by TIC10 Signals Foxo3a Nuclear Translocation, TRAIL Gene Induction, and Potent Antitumor Effects. Science Translational Medicine, 2013; 5 (171): 171ra17 DOI: 10.1126/scitranslmed.3004828

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Source: http://feeds.sciencedaily.com/~r/sciencedaily/top_news/~3/LkkHpOI2Zbs/130206162317.htm

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Senior Obesity And Weight Gain Shouldn't Be Ignored (STUDY)

Now that you're getting older, you no longer have to worry about cutting back on saturated fat or making sure you consume five to nine servings of vegetables a day, right? After all these years of counting calories, surely you no longer have to fret over your weight, right? Wrong! A new study finds that obese seniors are at greater risk of death than their younger overweight counterparts.

Previous research had indicated that an elevated BMI (Body Mass Index) at age 65 and older wouldn't impact one's lifespan and that it may actually extend it. But a new study has discovered the contrary, finding that, as obese Americans grow older, their risk of death grows greater.

Dr. Ryan Masters and Dr. Bruce Link at Columbia University?s Mailman School of Public Health, in collaboration with Dr. Daniel Powers at the University of Texas, published the results of the study online this week in the American Journal of Epidemiology.

The researchers argue that previous studies of longevity and obesity were biased due to limitations of the National Health Interview Survey, or NHIS, which provides information on obesity. For example, the survey excludes those who are institutionalized, such as in a hospital or nursing home -- a segment largely made up of seniors. Consequently, the data is overrepresented by older respondents who are healthy, including the relatively healthy obese. What?s more, many obese people fail to make it to age 65 and therefore don't live long enough to participate in studies of older populations.

?Obesity wreaks so much havoc on one?s long-term survival capacity that obese adults either don?t live long enough to be included in the survey or they are institutionalized and therefore also excluded. In that sense, the survey data doesn?t capture the population we?re most interested in,? says Masters, a Robert Wood Johnson Foundation Health & Society Scholar at Columbia?s Mailman School and the study?s first author.

In his analysis Masters studied data from nearly 800,000 adults between 1986 and 2004. The result: risk for death from obesity climbed with age.

Masters told Huff/Post50 that the level of obesity also has an impact on mortality.

"So we compared the survival of respondents with a normal or overweight BMI to respondents in [various] grades of obesity. Mortality risk increases in a successive manner, with higher BMI conferring a higher mortality risk," he said. "These results are consistent with existing evidence. So, yes, 'how' obese one is certainly matters, in a logically consistent way."

When asked how much one's mortality risk goes up due to obesity over the age of 65, Masters supplied the following information to Huff/Post50:

Grade 1 Obesity (BMI of 30.0 to 34.9):
For both men and women, grade 1 obesity increased mortality risk at 65+ years by about 40 to 60 percent (or 1.4 to 1.6 times, respectively).

Grade 2 Obesity (BMI of 35.0 to 39.9):
Men's mortality risk at 65+ years was increased by about 80-100 percent (1.8 to 2.0x).
Women's mortality risk at 65+ years was increased by about 90-100 percent (1.9 to 2.0x).

Grade 3 Obesity (BMI over 40):
Men's mortality risk at 65+ years was increased by about 160 to 260 percent (2.6 to 3.6x).
Women's mortality risk at 65+ years was increased by about 160 to 180 percent (2.6 to 2.8x).

Earlier on HuffPost50:

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Source: http://www.huffingtonpost.com/2013/02/06/senior-obesity-weight-gain-affects-longevity_n_2624987.html

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Afghan boys from nominated film to walk red carpet

KABUL, Afghanistan (AP) ? Fawad Mohammadi has spent half his life peddling maps and dictionaries to foreigners on a street of trinket shops in Kabul. Now the 14-year-old Afghan boy with bright green eyes is getting ready for a trip down the red carpet at the Oscars.

It will also be his first time out of the country and his first time on a plane.

Mohammadi was plucked from the dingy streets of the Afghan capital to be one of the main stars of "Buzkashi Boys," a coming-of-age movie filmed entirely in a war zone and nominated in the Best Live Action Short Film category.

The movie is about two penniless young boys ? a street urchin and a blacksmith's son ? who are best friends and dream of becoming professional players of buzkashi, a particularly rough and dangerous game that somewhat resembles polo: Horseback riders wrangle to get a headless goat carcass into a circular goal at one end of the field.

It's also part of an American director's effort to help revive a film industry devastated by decades of civil war and by the Taliban, an Islamic fundamentalist movement that banned entertainment and burned films and theaters during its five years in power.

Sam French, a Philadelphia native who has lived in Afghanistan for about five years, said his 28-minute movie was initially conceived as a way of training local film industry workers ? the first installment in his nonprofit Afghan Film Project.

"We never dreamed of having the film come this far and get an Oscar nomination," French, 36, said in a telephone interview from Los Angeles, where he is preparing for the Feb. 24 Academy Awards and raising money to fly the two young co-stars in for the ceremony.

The two boys playing the main characters ? Mohammadi and Jawanmard Paiz ? can barely contain their excitement about going to the Oscars.

"It will be a great honor for me and for Afghanistan to meet the world's most famous actors," said Mohammadi, whose real-life dream is to become a pilot. He's also hoping to go see the cockpit during the flight.

The farthest Mohammadi has ever traveled was to the northern Afghan city of Mazar-i-Sharif when he was younger.

Mohammadi's father died a few years ago, leaving him with his mother, five brothers and a sister. He started selling chewing gum when he was about 7 years old and soon expanded his trade to maps and dictionaries.

He learned to speak English hustling foreigners on Chicken Street, the main tourist area in Kabul with shops selling multicolor rugs, lapis bowls and other crafts and souvenirs, and gained a reputation for being polite, helpful and trustworthy. He was even able to enroll in a private school, thanks to the generosity of some other foreigners unrelated to the film project.

In the movie Mohammadi plays the blacksmith's son, Rafi, whose father wants him to follow in his footsteps.

"His life was so much harder than mine," Mohammadi said. "The blacksmith made him go out on the streets. I came myself here (to Chicken Street). My family didn't make me come. I wanted to make money to feed myself and to feed my family. He didn't have a home. They lived in the blacksmith shop."

Ironically it's not Mohammadi but Paiz, the youngest son of a well-known Afghan actor, who plays the homeless boy Ahmad.

Paiz, also 14, already was an experienced actor: He's appeared in films since the age of 5 and has gone to the Cannes Film Festival.

Paiz and Mohammadi had a lot to learn from each other and became friends. He gave Mohammadi tips for acting and handling himself in live interviews, while Fawad taught him about life outside his sheltered surroundings.

"When I saw Fawad was such a good actor even though he was a street boy and he was so brave in acting, I was very surprised and I said to myself, 'Everybody can achieve what they desire to do,'" Paiz said during an interview this week, shivering in the snow-covered courtyard of the Afghan Film Institute while a local TV series was being filmed nearby.

French, who co-wrote the script and produced "Buzkashi Boys" with Martin Roe of the Los Angeles-based production company Dirty Robber, launched a fundraising drive that's raised almost $10,000 so far to help bring the boys to Los Angeles for the ceremony. Any extra money will be placed in a fund to provide for Mohammadi's education and help his family. The boys will travel with an escort and will stay with the extended Afghan family of one of the film's producers, French said.

French said he's aware of the pitfalls in working with child actors from developing countries.

The makers of "Slumdog Millionaire," the rags-to-riches blockbuster about three poor Indian children, have struggled to make a better life for the young stars, and four boys who acted in "The Kite Runner" had to leave Afghanistan out of concern they could be ostracized or subject to violence because of a rape scene in the movie.

French said he and others involved in the "Buzkashi Boys" took pains to involve the community and made sure to avoid any scenes that could be offensive.

"We're not filmmakers who just do a film and leave. We remain there and present," he said. "We had lots and lots of tea with lots and lots of people."

The Academy of Motion Picture Arts and Sciences says there have been three documentary features nominees filmed at least in part in Afghanistan since 2007 ? all about the U.S. military. The Kite Runner, which was nominated for original score in 2007, was set in Afghanistan but not filmed there.

Afghanistan had a burgeoning film industry starting in the early 20th century, but it suffered from fighting during the civil war and the Taliban campaign to stamp out entertainment. Actors and film industry workers like Paiz's father and the actor who plays the blacksmith, Wali Talash, fled the country. They returned only after the 2001 U.S.-led assault that ousted the Islamic movement and its al-Qaida allies.

Talash, 56, said he hopes the "Buzkashi Boys" will show the world the rich culture of Afghanistan, which too few in the world know beyond reports of roadside bombs and suicide attacks.

"I hope if this movie wins that it will be an earthquake that will shake the industry and help Afghan filmmakers get back on their feet," he said.

Mohammadi, meanwhile, says he knows the money and fame he earned from the movie can carry him only so far. He still sells maps, though not so often as before, because he has school.

"For my work I used to know a lot of foreigners and I still do, but before they used to know me as a map seller. Now they know me as an actor," he said, waving a plastic-covered map as weary Afghans walked by on the muddy street. "Most of them take pictures with me and sometimes they buy maps from me even if they don't need any just because they spotted me in the movie."

___

Associated Press writer Steve Loeper in Los Angeles contributed to this report.

___

Online:

Fundraising site ? https://rally.org/buzkashiboys

Film website ? http://www.buzkashiboys.com/

Source: http://news.yahoo.com/afghan-boys-nominated-film-walk-red-carpet-170403187.html

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Leighton Meester and Adam Brody: Dating!

Source: http://www.thehollywoodgossip.com/2013/02/leighton-meester-and-adam-brody-dating/

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Asian shares drop on euro zone worry, soft U.S. data

TOKYO (Reuters) - Asian shares, oil and the euro fell on Tuesday as investors took profits from recent rallies, while the yen got a respite from broad-based selling.

European markets are seen barely changed, with financial spreadbetters predicting London's FTSE 100, Paris's CAC-40 and Frankfurt's DAX would open up nearly flat. But a 0.1 percent gain in U.S. stock futures suggested a firm open on Wall Street.

The MSCI's broadest index of Asia-Pacific shares outside Japan tumbled 0.9 percent, dragged lower by a steep 1.7 percent fall in Hong Kong shares. The pan-Asian index climbed to a 18-month high on Monday.

Japan's benchmark Nikkei stock average closed down 1.9 percent, after scaling a 33-month high on Monday.

Positive data from China failed to brighten the bearish mood, after the Standard & Poor's 500 Index had its worst day since November on Monday on discouraging U.S. factory orders and worries that a potential political shake-up could disrupt the euro zone's efforts to resolve its debt crisis.

Analysts and traders said selling was a correction to markets rallying on receding tail risks such as growing euro zone stability and an improving global economic outlook, while global monetary easing still underpinned sentiment.

"This move in equities ... looks to be a healthy correction, nothing more," said Richard Yetsenga, Head of Global Markets at ANZ Research, adding that downside risk would likely convince major central banks globally to stick to easy policy.

In China, the HSBC services purchasing managers' index rose to a four-month high of 54 in January from December's 51.7, underlining confidence in the world's second-biggest economy, which is expected to grow 8.1 percent this year, off a 13-year low of 7.8 percent hit in 2012.

"The data globally is unquestionably better but the recovery still seems gradual. (China) hit the bottom and they had a bit of a bounce but nothing much else happened. We don't really seem to have preconditions for a much stronger bounce than that (8 percent growth)," Yetsenga said.

The Australian dollar fell 0.3 percent to $1.0405 after the Reserve Bank of Australia kept its cash rate steady at 3.0 percent, as expected, having just cut in December. Australian shares fell 0.5 percent but trimmed some earlier losses after the RBA's rate decision.

The euro took the brunt of renewed focus on the euro zone problems, having risen 2.3 percent so far this year against the U.S. dollar, up about 5.4 percent against sterling and 1.8 percent higher against the Australian dollar.

The euro eased 0.2 percent to $1.3485, retreating further from Friday's 14-1/2-month peak of $1.3711, ahead of the European Central Bank's policy meeting on Thursday.

"Markets have been increasingly comfortable with European risks over the past few months and are largely not positioned for this increase in political problems. The outcomes in Spain and Italy are far from certain and may represent stumbling blocks for further expansion in risk appetite," Barclays Capital said in a research note.

Spain's opposition party on Sunday called for Prime Minister Mariano Rajoy to resign over corruption allegations, which Rajoy denies, pushing Spanish 10-year bond yields to six-week highs.

In Italy, 10-year Italian government bond yields hit their highest since late December, as chances of former prime minister Silvio Berlusconi regaining power raised worries about Rome's ability to fix its fiscal problems.

The yen took a breather, firming from lows against a broad range of currencies.

The dollar steadied at 92.36 yen after scaling its highest since May 2010 of 93.185 on Monday, while the euro eased 0.1 percent to 124.53 yen, off its loftiest since April 2010 of 126.97 hit on Friday.

"Markets are broadly undergoing a correction and the euro is definitely facing profit-taking, given the pace of its climb. Worries about the euro zone debt crisis always remain a downside risk for the euro, and could push it lower to $1.32-$1.33," said Hiroshi Maeba, head of FX trading Japan at UBS in Tokyo. "But the trend is still upward for dollar/yen, cross/yen. The dollar could reach 95 yen by the end of the month."

As long as markets hold out expectations for the Bank of Japan to implement aggressive monetary easing to beat decades of deflation in Japan, the yen will stay pressured. Any correction to the dollar's rise against the yen was also be seen as shallow, with many traders and analysts seeing a firm floor around 87-88 yen.

Asian credit markets faltered with the plunge in equities, widening the spread on the iTraxx Asia ex-Japan investment-grade index by three basis points.

Brent crude slipped towards $115 per barrel, giving up some of its gains from the last three weeks, on renewed euro zone worries and a slightly firmer dollar.

(Editing by Eric Meijer)

Source: http://news.yahoo.com/asian-shares-drop-euro-zone-worry-soft-u-034800107--finance.html

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Records: Veteran had been in mental hospital

In this April 6, 2012, photo, former Navy SEAL and author of the book ?American Sniper?, Chris Kyle poses in Midlothian, Texas. A Texas sheriff has told local newspapers that Kyle has been fatally shot along with another man on a gun range, Saturday, Feb. 2, 2013. (AP Photo/The Fort Worth Star-Telegram, Paul Moseley)

In this April 6, 2012, photo, former Navy SEAL and author of the book ?American Sniper?, Chris Kyle poses in Midlothian, Texas. A Texas sheriff has told local newspapers that Kyle has been fatally shot along with another man on a gun range, Saturday, Feb. 2, 2013. (AP Photo/The Fort Worth Star-Telegram, Paul Moseley)

This photo provided by the Erath County Sheriff?s Office shows Eddie Ray Routh. He was charged with murder in connection with a shooting at a central Texas gun range that killed former Navy SEAL and "American Sniper" author Chris Kyle and Chad Littlefield, the Texas Department of Public Safety said Sunday, Feb. 3, 2013. (AP Photo/ Erath County Sheriff's Office)

View of buildings on the property of Rough Creek Lodge photographed Sunday, Feb. 3, 2013. Chris Kyle and Chad Littlefield were found murdered at the gun range on the property. (AP Photo/The Fort Worth Star-Telegram, Richard W. Rodriguez)

In this April 6, 2012, photo, former Navy SEAL and author of the book ?American Sniper? poses in Midlothian, Texas. A Texas sheriff has told local newspapers that Chris Kyle has been fatally shot along with another man on a gun range, Saturday, Feb. 2, 2013. (AP Photo/The Fort Worth Star-Telegram, Paul Moseley)

Map showns path of texas gunman following a double shooting

FORT WORTH, Texas (AP) ? The Iraq War veteran charged with killing a former Navy SEAL sniper and his friend on a Texas shooting range had been taken to a mental hospital twice in the past five months and told authorities he was suffering from post-traumatic stress disorder, police records show.

Eddie Ray Routh, 25, also told his sister and brother-in-law after the shootings that he "traded his soul for a new truck," according to an Erath County arrest warrant affidavit obtained by WFAA-TV. Police said Routh was driving the truck of victim and ex-Navy SEAL Chris Kyle at the time of his arrest.

Routh is charged with one count of capital murder and two counts of murder in the shooting deaths of Kyle, author of the best-selling book "American Sniper," and his friend Chad Littlefield at a shooting range Saturday in Glen Rose. He is on suicide watch in the Erath County Jail, where he's being held on $3 million bail, Sheriff Tommy Bryant said.

Routh, a member of the Marines Corps Reserve, was first taken to a mental hospital Sept. 2 after he threatened to kill his family and himself, according to police records in Lancaster, where Routh lives. Authorities found Routh walking nearby with no shirt and no shoes, and smelling of alcohol. Routh told authorities he was a Marine veteran who was suffering from post-traumatic stress disorder.

"Eddie stated he was hurting and that his family does not understand what he has been through," the report says.

Routh's mother told police her son had been drinking and became upset when his father said he was going to sell his gun. She said Routh began arguing with them and said he was going to "blow his brains out."

Police took Routh to Green Oaks Hospital for psychiatric care.

Dallas police records show Routh was taken back to the same mental hospital in mid-January after a woman called police and said she feared for Routh's safety.

Green Oaks will not release patient information, citing privacy laws. Most people brought by police to the hospital are required to stay at least 48 hours.

In another brush with authorities, Lancaster police in May responded to a burglary reported by Routh's mother that included nine pill bottles. Police say Routh was involved but no other details were available.

Authorities say Routh, Kyle and Littlefield arrived at the sprawling Rough Creek Lodge about 3:15 p.m. Saturday, and a hunting guide called 911 about two hours later after discovering the bodies. Kyle and Littlefield were shot multiple times, and numerous guns were at the scene, according to the affidavit.

Routh drove to his sister's house, and told her he had killed two people and that he planned to drive to Oklahoma to evade Texas authorities, the affidavit said. Routh's sister then called police, and he was arrested after a short police pursuit in Lancaster.

Jailers used a stun gun on Routh on Sunday night after he appeared ready to assault them when they entered his cell after he refused to return his food tray, the sheriff said. Then they put Routh in a chair that restrains his arms and legs in his solitary confinement cell, Bryant said.

Bryant said Routh has an attorney but hasn't met with him at the jail in Stephenville, about 75 miles southwest of Fort Worth.

Attempts by The Associated Press to reach Routh's mother and sister were unsuccessful Monday.

Sundae Hughes, an aunt of Routh's, said she watched him grow up but hasn't seen him since his high school graduation in 2006. Hughes was in disbelief that her nephew could be involved in such an incident.

"He has a kind heart (and was) someone willing to jump in and help, no matter what it was," she said.

Routh joined the Marines in 2006 and rose to the rank of corporal in 2010. His military specialty was small-arms technician, commonly known as an armorer. He had been stationed at Camp Lejeune, N.C., and served in Iraq from 2007-08 and in the Haiti disaster relief mission in 2010.

He is now in the individual ready reserve. He could be called to duty, but it's uncommon unless he volunteers, 1st Lt. Dominic Pitrone of the Marine Forces Services public affairs office said.

Travis Cox, director of FITCO Cares ? the nonprofit that Kyle set up to give in-home fitness equipment to physically and emotionally wounded veterans ? said he believes that Kyle and Littlefield were helping Routh work through PTSD.

Cox didn't know how Routh and Kyle knew each other. He said the shooting range event was not a FITCO session.

Kyle, 38, left the Navy in 2009 after four tours of duty in Iraq, where he earned a reputation as one of the military's most lethal snipers. "American Sniper" was the No. 3 seller of paperbacks and hardcovers on Amazon as of Monday, and the hardcover was out of stock.

Littlefield, 35, was Kyle's friend, neighbor and "workout buddy," and also volunteered his time to work with veterans, Cox said.

__

Stengle reported from Midlothian, Texas. Associated Press writers Juan Carlos Llorca in El Paso, Texas; Christopher Sherman in McAllen, Texas; Martha Waggoner in Raleigh, N.C.; and AP researcher Rhonda Shafner contributed to this report.

Associated Press

Source: http://hosted2.ap.org/APDEFAULT/3d281c11a96b4ad082fe88aa0db04305/Article_2013-02-04-Sniper%20Author-Shooting/id-d19c8143e9d94ff185a6313f38bf0a7a

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Video: Researchers capture key moments in cell death

Monday, February 4, 2013

Scientists at the Walter and Eliza Hall Institute have for the first time visualised the molecular changes in a critical cell death protein that force cells to die.

The finding provides important insights into how cell death occurs, and could lead to new classes of medicines that control whether diseased cells live or die.

Cell death, called apoptosis, is important for controlling the number of cells in the body. Defects in cell death have been linked to the development of diseases such as cancer and neurodegenerative conditions. Insufficient cell death can cause cancer by allowing cells to become immortal while excessive cell death of neurons may be a cause of neurodegenerative conditions.

Dr Peter Czabotar, Professor Peter Colman and colleagues in the institute's Structural Biology division, together with Dr Dana Westphal from the institute's Molecular Genetics of Cancer division, made the discovery which is published in the latest edition of the journal Cell.

Dr Czabotar said activation of the protein Bax had long been known to be an important event leading to apoptosis, but until now it was not known how this activation occurred. "One of the key steps in cell death is that holes are punched into a membrane in the cell, the mitochondrial membrane," Dr Czabotar said. "Once this happens the cell is going to go on and die. Bax is responsible for punching the holes in the mitochondrial membrane and visualising its activation brings us a step closer to understanding the mechanics of cell death."

Using the Australian Synchrotron, Dr Czabotar and colleagues were able to obtain detailed three-dimensional images of Bax changing shape as it moved from its inactive to active form. The active form ruptures mitochondrial membranes, removing the cell's energy supply and causing cell death.

"By using the powerful X-ray beams created by the synchrotron, we obtained structures of Bax that were really exciting," Dr Czabotar said. "Bax is activated when small protein fragments called BH3-peptides bind to it. We saw that these peptides open up the Bax molecule like a key unlocking a padlock. This unlocked form of Bax can bind to another Bax molecule, which can then form larger Bax complexes that can go on to break up membranes in the cell.

"As well as explaining the detail of how cell death occurs, our research could provide clues about how to design potential new therapeutic agents that target Bax," Dr Czabotar said. "Now that we can see how Bax changes its shape to move from the inactive to the active form, it may be possible to block Bax activation, to prevent cell death in conditions such as neurodegenerative disorders, where illness is caused by excessive cell death. Similarly, agents that drive Bax into its active form could force immortal cells such as cancer cells to die, providing the basis for a potential new class of anti-cancer agents."

###

Walter and Eliza Hall Institute: http://www.wehi.edu.au/

Thanks to Walter and Eliza Hall Institute for this article.

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Source: http://www.labspaces.net/126599/Video__Researchers_capture_key_moments_in_cell_death

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