�Genes that inhibit the spontaneous development of genus Cancer are called tumor suppressor genes. One of the major neoplasm suppressors is p53, a protein that acts in the cell nucleus to control the expression of other genes whose products can bottle up cell proliferation (increase in cell number) and cell growth (increase in jail cell size). Abnormal cell proliferation and growth are characteristics of cancer the Crab. Scientists previously knew which p53 butt genes stamp down cell proliferation, but those required for inhibition of cell growth were unknown.
New work by researchers at the University of California, San Diego School of Medicine describes the mechanism by which p53 regulates cells and protects them against DNA damage that might pb to crab. The sketch shows that two p53 target genes called Sestrin1 and Sestrin2 provide an important contact between p53 and a protein kinase called mTOR, a central regulator of cell growth. mTOR is the object for the inhibitory activeness of the immunosuppressive drug rapamycin, of late found to have antineoplastic activity.
The discovery by Michael Karin, Ph.D., professor of pharmacology in the Laboratory of Gene Regulation and Signal Transduction at the UC San Diego School of Medicine, and postdoctoral research fellow Andrei V. Budanov, Ph.D, will be published in the August 8 way out of the journal Cell.
"The two Sestrin genes appear to be the missing piece of the mystifier that explains how p53 can inhibit the mTOR pathway and thereby negatively regulate cell growth," aforesaid Budanov, wHO added that while the connection 'tween the deuce was known, the mechanism wasn't previously understood. The finding english hawthorn prove to be very important in scientists' search for novel inhibitors that stop or slow cancer tumor growth.
In fact, Budanov obtained results suggesting that the two Sestrins whitethorn be tumour suppressors in their have right. DNA damage (genotoxic stress) triggers two major biological responses in mammals: cell oscillation arrest, which allows repair and survival of the cell; and apoptosis or cell death a sue in which damaged cells, which could otherwise pass on rise to cancer, ar eliminated.
The major tumor suppresser p53 can either inhibit cell proliferation and cubicle growth or induce cell death; its different functions are mediated through numerous target genes and reckon on the extent of damage to the cellphone. As more than than half of human cancers either lost p53 expression or express a defective edition of p53, understanding the mechanisms by which p53 accomplishes its critical tumour suppressive function may lead to development of modern cancer preventives and therapeutics.
The UCSD researchers wondered what target genes would grant p53 to inhibit mobile phone growth. The central regulator of cell growth is the protein kinase mTOR, whose activity is inhibited by rapamycin, which is used in prevention of organ transplant rejection. Recent work indicates that rapamycin may besides be used to inhibit the growth of tumors and give them more susceptible to chemotherapy.
Previous studies conducted by Budanov showed that the Sestrin1 and Sestrin2 proteins, which are expressed in response to genotoxic stress, serve a protective single-valued function and may also curb cell growth. It has also been shown that Sestrin1 and 2, as well as their master regulator p53, can restraint the accumulation of reactive oxygen species (ROS), which play of import roles in cell signaling. Under genotoxic stress, ROS levels can increase dramatically, which can lead to significant damage to cell structures, resulting in oxidative stress.
"We have now shown that in addition to controlling ROS accumulation, Sestrins and p53 also inhibit cell growth by inhibiting the activity of mTOR. This explains how p53 functions as a potent regulator of so many aspects of cell physiology and provides protection against DNA wrong and tension," said Budanov.
Knockout mouse models of Sestrin1 and 2 will be an important tool for studying their role in carcinogenesis, according to the researchers. Karin adds that small molecules that mimicker the molecular actions of the Sestrins can be used to control cell metabolism and regain control over malignant neoplastic disease cells that have lost their p53.
Funding for this study was provided by grants from the Tobacco Related Disease Research Program, the National Institute of Environmental Health Science and the Superfund Basic Research Program.
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