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Old 04-09-2013, 07:49 PM
Dross Dross is offline
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Default Circadian Rhythm and the Myc oncogene.

The Myc oncogene can disrupt the 24-hour internal rhythm in cancer cells. Postdoctoral fellow Brian Altman, PhD, and graduate student Annie Hsieh, MD, both from the in the lab of Chi Van Dang, MD, PhD, director of the Abramson Cancer Center, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, present their data in the "Metabolic Pathway Regulation in Cancer" session at the 2013 American Association for Cancer Research meeting, Washington, D.C., April 9, 2013.

Timing of the body's molecular clock in normal cells synchronizes the cellular need for energy with food intake during our sleep-wake cycle. Timing matters to the study of cancer in two ways. First, toxicity to some chemotherapy drugs is related to time of day. For example, a cancer drug called 5-flourouracil is less toxic if given to a patient at night because the liver enzymes that detoxify it are more abundant at night.

Second, several circadian rhythm genes have been implicated as tumor suppressors, although those exact connections are as yet unclear. Other researchers have also observed that many, but not all, cancer cell cultures lack proper circadian rhythm.

"Our hypothesis is that disrupting circadian rhythm benefits cancer cells by unleashing their metabolism from the constraints of the molecular clock," says Altman. "In this regard, cancers don't sleep; they don't rest."

The Penn study deals with the relationship of clock proteins in peripheral tissues associated with three types of cancer cells. The researchers surmise that Myc may affect circadian rhythm by promiscuously binding to promoter regions in key genes for maintaining circadian rhythm. In fact, using a well known genome browser they confirmed that Myc binds to circadian genes.

The Penn team also found that Myc upregulates another clock-regulated protein called NAMPT, potentially leading to dysregulated Sirt1 activity, another protein that is part of the complicated molecular clock.

Inhibiting NAMPT downstream of Myc also led to changes in circadian gene expression, suggesting a role for the modulation of other proteins downstream of Myc in throwing a wrench in the clock's gears.

Using cells from cultures of neuroblastoma, osteosarcoma, and hepatocellular carcinoma, which all overexpress Myc, they found that the abundance of Myc specifically upregulated the circadian protein Rev-erbα. This protein in turn suppressed the oscillation of Bmal1 messenger RNA and decreased expression of the main clock protein Bmal1.

What's more, the disrupted circadian oscillations in the Myc-expressing cancer cells could be partially rescued by inhibiting expression of Rev-erbα.

"Our data suggest that Myc-driven cancers have altered circadian oscillation due to upregulation of Rev-erbα and NAMPT, and that these Myc cancers may be good candidates for chronotherapy," says Altman. "This work ties together the study of cell metabolism and cancer chronotherapy – If cells don't have to 'rest," they may replicate all the time, with no breaks at all. "

"The understanding of these basic mechanisms from our work should lead to better cancer treatment strategies that reduce side effects and increase effectiveness" says Hsieh.

Reference: This study was funded by the National Cancer Institute (R01CA051497, R01CA57341) and the Leukemia and Lymphoma Society (636311).

Citation: University of Pennsylvania School of Medicine. "Understanding How Oncogenes Affect The Body Clock May Help Create Better Cancer Treatments." Medical News Today. MediLexicon, Intl., 11 Apr. 2013.

Last edited by gdpawel : 04-11-2013 at 11:41 AM. Reason: posted full article in forum board
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Old 04-09-2013, 09:08 PM
gdpawel gdpawel is offline
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Default Texas A&M researchers find new mechanism for circadian rhythm

Molecules that may hold the key to new ways to fight cancer and other diseases have been found to play an important role in regulating circadian rhythm, says Liheng Shi, a researcher in Texas A&M's Department of Veterinary Integrative Biosciences.

Circadian rhythm is the roughly 24-hour cycle of physiological activities of humans, animals and even bacteria, Shi explains.

He and colleagues have had their research, currently focusing on the circadian rhythm in chickens' eyes, published in the "Journal of Biological Chemistry." Chicken eyes have a lot in common with human eyes.

"The prefix 'photo-' in photoreceptors means light, and photoreceptors in animals' eyes receive light signals and then translate them into signals that their brain can understand, and that is how they see," he explains.

Shi notes there are two kinds of photoreceptors – cone photoreceptors and rod photoreceptors, named for the shape they resemble.

Some channels that scientists call L-VGCCs are important to the circadian rhythm in chickens' eyes. These channels are important because they are the pathways through which messages go in and out of photoreceptors, and these messages are crucial to the proper functioning of the eye.

A group of proteins (L-VGCCα1C) carries the messages in and out. At night, they get more work done than during the day to "prepare chickens' eyes for another day's busy work" and "tell various parts of the eye to adjust to the darkness," explains Shi, who holds a post-doctoral position under the mentorship of Gladys Ko, one of the coauthors of the article.

These proteins are controlled by messengers called mRNA, and they are especially active, raising the question of why, he says.

"There must be an explanation," Shi says, "and we found a possible answer."

The answer lies in a sibling of the messenger named microRNA-26a, a "small guy" in the RNA family.

"During the day, the 'naughty small guy' crawls onto the back of his brother mRNA, so his brother cannot concentrate on his work," the Texas A&M researcher explains. "At night, however, he lets his brother go, so his brother focuses on his work and gets more work done."

He advises not to "look down" on the mRNA. "If they quite their job, the chicken may become blind," Shi adds. "Besides regulating circadian rhythm, the microRNA family also influence cancer development, cell division, heart disease, and so on."

"What we know about microRNAs is probably only a tip of the iceberg," the Texas A&M postdoc says. "As we get to know more about them, these small guys may be able to help us diagnose and treat many diseases."
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Old 04-09-2013, 09:10 PM
gdpawel gdpawel is offline
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Default Modification Of Circadian Rhythms For Potential Treatment Of Disorders

UC Irvine-led studies have revealed the cellular mechanism by which circadian rhythms - also known as the body clock - modify energy metabolism and also have identified novel compounds that control this action. The findings point to potential treatments for disorders triggered by circadian rhythm dysfunction, ranging from insomnia and obesity to diabetes and cancer.

UC Irvine's Paolo Sassone-Corsi, one of the world's leading researchers on the genetics of circadian rhythms, led the studies and worked with international groups of scientists. Their results are detailed in two companion pieces appearing this week in the early online edition of the Proceedings of the National Academy of Science.

"Circadian rhythms of 24 hours govern fundamental physiological functions in almost all organisms," said Sassone-Corsi, the Donald Bren Professor of Biological Chemistry. "The circadian clocks are intrinsic time-tracking systems in our bodies that anticipate environmental changes and adapt themselves to the appropriate time of day. Disruption of these rhythms can profoundly influence human health."

He added that up to 15 percent of people's genes are regulated by the day-night pattern of circadian rhythms.

In one study, Sassone-Corsi and colleagues found that the biological clock controls enzymes localized in the mitochondrion, a cellular structure devoted to energy metabolism. This government occurs through acetylation of proteins, a process that operates as a switch to turn genes on and off in cells based upon the cells' energy usage.

Some of the most important acetylation events in cells are dictated by an enzyme protein called SIRT1, which senses energy levels in the cell. Its activity is modulated by how many nutrients a cell is consuming. It also helps cells resist oxidative and radiation-induced stress. SIRT1 has been linked to the inflammatory response, diabetes and aging.

SIRT1 belongs to a class of genes that regulate chronic inflammation, cancer and aging. When SIRT1 is highly active, or over-expressed in mice, worms and fruit flies, their life spans are greatly increased. Recent studies also show that SIRT1 plays a positive role in stress resistance, metabolism, apoptosis and other processes involved in premature aging.

However, environmental stress such as cigarette smoke or pollution can decrease production of SIRT1 in the lungs.

Sassone-Corsi first showed the circadian rhythm-metabolism link in 2008 and 2009, and in this study, he and his colleagues reveal the metabolic pathways through which SIRT1 works.

"When the balance between clock proteins is upset, normal cellular function can be disrupted," said Sassone-Corsi, who also directs the Center for Epigenetics & Metabolism at UC Irvine.

In exploring how to regulate SIRT1 activity, Sassone-Corsi teamed with scientists from two research-and-development groups at GlaxoSmithKline - one in the United Kingdom and the other (called Sirtris) in the U.S. - to test proprietary small-molecule compounds that stimulate SIRT1.

In mouse studies, they were able to modulate the scale of circadian-driven gene function with the SIRT1-activating compounds, effectively governing the circadian cycle in a host of genes involved with the metabolic rate in cells. This research proves that small molecules can be used as a pharmacological strategy to control circadian disturbances and is a step toward the development of drugs that could target many conditions, including metabolic disorders, diabetes, cancer and aging.

References:

Postdoctoral researchers Selma Masri and Kristin Eckel-Mahan, graduate student Vishal Patel and Chancellor’s Professor Pierre Baldi of UC Irvine, along with Shahaf Peleg, Ignasi Forne, Andreas Ladurner and Axel Imhof of Germany’s University of Munich, as well as Sassone-Corsi, contributed to the study titled “The Circadian acetylome reveals regulation of mitochondrial metabolic pathways.” The National Institutes of Health, the National Science Foundation, INSERM and Sirtris provided support.

In addition to Sassone-Corsi, postdoctoral researcher Marina Bellet and laboratory assistant Marlene Cervantes of UC Irvine; Mohamed Boudjelal, Emma Watts, Danuta Mossakowska and Kenneth Edwards of GlaxoSmithKline; Giuseppe Astarita of Georgetown University; and Christine Loh, James Ellis and George Vlasuk of Sirtris contributed to the study titled “Pharmacological modulation of circadian rhythms by high-affinity SIRT1 activators.” The National Institutes of Health and INSERM provided support.

Citation: University of California - Irvine. "Modification Of Circadian Rhythms For Potential Treatment Of Disorders." Medical News Today. MediLexicon, Intl., 25 Jan. 2013
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Old 04-09-2013, 09:11 PM
gdpawel gdpawel is offline
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Default Circadian Physiology

The earlier in the day concept has some basis in cancer biology. Apparently, this "circadian" issue is talked alot in medical oncology. This is the first heard of it in radiation oncology.

Circadian physiology highlights the basic processes and latest research findings in circadian biology and describes how this knowledge applies to the timing for effective administration of medicines. The formal study of biological temporal rhythms is called chronobiology.

According to Wiki, photosensitive proteins and circadian rhythms are believed to have originated in the earliest cells, with the purpose of protecting the replicating of DNA from high ultraviolet radiation during the daytime. As a result, replication was relegated to the dark.

Circadian rhythms allow organisms to anticipate and prepare for precise and regular environmental changes; they have great value in relation to the outside world. The rhythmicity appears to be as important in regulating and coordinating internal metabolic processes, as in coordinating with the environment.

Many more genetic components of the biological clock are now known. Their interactions result in an interlocked feedback loop of gene products resulting in periodic fluctuations that the cells of the body interpret as a specific time of the day.

Circadian Rhythm: [url]http://en.wikipedia.org/wiki/Circadian_rhythm

Circadian Physiology: [url]http://www.circadian.org/book.html

Dictionary of Circadian Physiology: [url]http://www.circadian.org/dictionary.html
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