Navigation Links
Study reveals details of alternative splicing circuitry that promotes cancer's Warburg effect
Date:11/2/2011

Cold Spring Harbor, N.Y. Cancer cells maintain their life-style of extremely rapid growth and proliferation thanks to an enzyme called PK-M2 (pyruvate kinase M2) that alters the cells' ability to metabolize glucose a phenomenon known as the Warburg effect.

Professor Adrian Krainer, Ph.D., and his team at Cold Spring Harbor Laboratory (CSHL), who seek to reverse this effect and force cancer cells to regain the metabolism of normal cells, have discovered details of molecular events that cause cancer cells to produce PK-M2 instead of its harmless counterpart, an isoform called PK-M1. Their study, performed in collaboration with Professor Lewis Cantley, Ph.D., and his colleagues at Harvard Medical School and The Koch Institute, in Cambridge, Mass, appears on November 1 in the Journal of Molecular Cell Biology.

Both protein isoformsPK-M2 and PK-M1, the latter of which is found only in normal cellsare both encoded by the same gene, PK-M, in a mutually exclusive fashion via a process called alternative splicing. After the gene is transcribed to produce RNA, unneeded bits called introns are first spliced out. How the remaining bits, called exons, are stitched back together by the cell's splicing machinery decides which protein version is produced. In the case of the RNA transcript for PK-M RNA, the choice is between two exons: exon 9, found in PK-M1; and exon 10, whose inclusion results in PK-M2 production.

"In this study, our goal was to determine what exactly the splicing machinery looks for when it's trying to decide which exon to include and which exon to exclude," specifies Krainer. Following a series of experiments in which the team manipulated the two exons within a precursor form of the RNA PK-M by duplicating them, swapping their positions, etc., the scientists discovered that the signals for mutually exclusive splicing reside within the two exons themselves.

The exon 10-inclusion signal is a potent splicing "enhancer" a sequence of nucleotides or "bases" that differs from its counterpart in exon 9 by a mere two nucleotides. These two so-called "wobble bases" are responsible for recruiting a splicing protein called SRSF3, the team has found. "Our discovery that SRFS3 plays a role in promoting the Warburg effect is consistent with other studies that recently identified this protein as having oncogenic properties and found it to be produced at high levels in ovarian and cervical cancer cells," says Krainer.

SRSF3 itself might not make for a good therapeutic target, as it oversees splicing in numerous other genes unrelated to cancer. But Krainer's team is focusing on finding ways to redirect splicing to force cancer cells to preferentially include exon 9 and thereby produce PK-M1 instead of PK-M2. The team has previously been successful in correcting a splicing defect that causes the neuromuscular disease, spinal muscular atrophy, using "antisense" technologywhich involves synthetic nucleotide sequencesto redirect splicing to force the inclusion of a single exon.

"The task at hand is more challenging because it involves mutually exclusive splicing in which one exon has to be included while the inclusion of the other exon has to be prevented," explains Krainer.


'/>"/>

Contact: Hema Bashyam
bashyam@cshl.edu
516-367-6822
Cold Spring Harbor Laboratory
Source:Eurekalert

Related medicine news :

1. Exenatide (Byetta) has rapid, powerful anti-inflammatory effect, UB study shows
2. Cancer Risk Doubles After Organ Transplant, Study Finds
3. Yoga Gets Women With Back Pain Moving: Study
4. Study finds overweight teens want to lose weight, going about it the wrong way
5. Many radiologists disagree on management of incidental findings, study finds
6. Handheld Metal Detectors Dont Seem to Affect Pacemakers: Study
7. Study shows no increased risk of breast cancer for non-carriers in families with BRCA gene mutation
8. The freshman 15 is just a myth, nationwide study reveals
9. First-of-its-kind study creates new tool for targeted cancer drug development
10. Study finds community counseling reduced the prevalence of TB on a budget
11. Practice Doesnt Always Make Perfect, Study Suggests
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:8/17/2017)... ... 17, 2017 , ... Dr. Charles W. Grimsley’s new book ... paperback, 9781498497626; $7.99, eBook, 9781498497633) focuses on the treatment of veterans diagnosed with ... forgiveness, through a progressive journey toward healing. This book will help readers learn ...
(Date:8/17/2017)... ... , ... Advice Media, the industry leader in digital marketing for medical practices, has been recognized ... included in the Inc. 5000 for the second time in two years. Shawn Miele, Chief ... 5000 rankings for the second year in a row. It’s extremely difficult to make this ...
(Date:8/16/2017)... ... 16, 2017 , ... Summer days spent with family are priceless. Since August ... suggestions for enjoying the season of sunshine. Add trying something new to this summer’s ... join in on the fun. , Try Something New , Choose ...
(Date:8/16/2017)... ... ... Ten outstanding teachers in the Greater Houston area will be named one ... by a Houston Texans player, two tickets to a Texans game, and other prizes. ... texanschecking.com/stars to nominate their favorite teacher with an essay of no more than 500 ...
(Date:8/16/2017)... ... , ... In a recent survey, eighty-two percent of women reported having cellulite, ... can't always be eliminated by diet and exercise alone, and now for the first ... Dr. Kenneth Rothaus has recently added Cellulaze™ to his practice in New ...
Breaking Medicine News(10 mins):
(Date:8/8/2017)... TEL AVIV, Israel, Aug. 8, 2017  BioLineRx Ltd. ... and immunology, today reports its financial results for the ... and achievements during the second quarter 2017 and to ... on multiple clinical development programs for the Company,s lead ... Phase 3 pivotal study with BL-8040 as novel stem ...
(Date:8/7/2017)... Diplomat Pharmacy, Inc. (NYSE: DPLO ) today announced ... Aug. 7, 2017. ... and will serve as president emeritus during a planned, 90-day ... multiple leadership roles since he joined Diplomat with the acquisition ... decisive, strategic leadership which continues to benefit our patients and ...
(Date:8/4/2017)... Aug. 3, 2017  Agragen, LLC, a ... in the biopharmaceutical, nutraceutical, and aquacultural feed sectors, ... its lead drug candidates, AGR131.  This drug is ... from the blood of patients suffering from inflammatory ... bowel disease. ...
Breaking Medicine Technology: