Navigation Links
‘SKIP’-ing splicing forces tumor cells to undergo programmed cell death
Date:4/1/2011

LA JOLLA, CAWhen cells find themselves in a tight spot, the cell cycle regulator p21 halts the cell cycle, buying cells time to repair the damage, or if all else fails, to initiate programmed cell death. In contrast to other stress-induced genes, which dispense with the regular transcriptional entourage, p21Cip1 still requires SKIP, a transcription elongation factor that also helps with the editing of transcripts, to be expressed, found researchers at the Salk Institute for Biological Studies.

In the absence of SKIP, the expression of p21Cip1 is rapidly down-regulated, predisposing cells to undergo programmed cell death, especially when faced with DNA damage-inducing chemotherapeutic agents. Their findings, reported in the April 1, 2011 issue of Genes & Development, not only define a new step that controls programmed cell death in cancer cells, but also suggest new approaches to enhance the efficacy of chemotherapeutic drugs.

"Interestingly, SKIP levels decline in cells treated with flavopiridol, which is currently in clinical trials as an anticancer agent for leukemia, and as a combination therapy for solid tumors," says Katherine A. Jones, Ph.D., a professor in the Regulatory Biology Laboratory, who led the study. "Our findings might help explain why flavopiridol works so well in combination with other cytotoxic drugs. Loss of SKIP sensitizes cancer cells to the apoptotic effects of DNA damage-inducing anticancer drugs."

The DNA in our cells is under constant attack from reactive chemicals generated as by-products of cellular metabolism. In addition, it is assaulted by x-rays, ultraviolet radiation from the sun, and environmental carcinogens such as tobacco smoke. If a cell suffers non-repairable injury it activates a built-in "auto-destruct" mechanism, known as programmed cell death or apoptosis. It eliminates abnormal cells from the body before they can cause disease, including cancer.

As a first-responder, the transcription factor p53 is called to action when cells experience stressful conditions. Depending on the situation, p53 then turns on genes that halt cell division to allow time for repairs, such as p21Cip1, or when all rescue attempts prove futile, order the cell to commit suicide by turning on pro-apoptotic genes such as PUMA.

"It is the timing and duration of expression of the set of p53 target genes that are turned on, which strongly influences cell fate decisions," says Jones, who likes to compare PUMA, which takes its time to come online, and p21Cip1, which quickly snaps into action in response to damage, to Aesop's fable of the tortoise and the hare. "Cell cycle arrest genes are poised for immediate action, whereas pro-apoptotic genes go slow but steady."

Even before cell damage occurs, these genes differ in the number and composition of their pre-loaded transcription complexes. These multi-protein assemblies, called RNA polymerase II (Pol II), slide along the DNA's double helix, reading the genetic code and transcribing it into RNA, which is used as a blueprint to build proteins, or as a switch to regulate other genes. But Pol II is prone to stalling in the middle of transcribing genes and needs to be prodded along by elongation factors such as SKIP. "Under stressful conditions everything changes," explains Jones. "Elongation factors seem to be no longer necessary for transcription."

But SKIP influences gene expression in more than one way. It also plays an important role during the splicing process, which removes intervening sequences or introns, and joins the remaining pieces or exons to form a mature messenger RNA that can now be used to produce protein.

It is the splicing function that p21Cip1 cannot do without, revealed the experiments by postdoctoral researchers Yupeng Chen, Ph.D., and Lirong Zhang, Ph.D. "SKIP is critical for splicing and expression of p21Cip1, but not for PUMA or any of the other p53-induced genes we looked at in colon cancer and osteosarcoma cells," says Chen. He found that SKIP recruits a critical splice factor to the p21 gene, while the same factor finds its way to the PUMA gene without SKIP's help. As a consequence, the depletion of SKIP induced apoptosis, which was most pronounced in cells subjected to DNA damage.

"Many chemotherapeutic drugs work by inducing apoptosis," says Zhang. "Combining them with small molecules that inhibit splicing of the p21 mRNA may boost their efficiency of forcing tumor cells to undergo programmed cell death."


'/>"/>
Contact: Gina Kirchweger
Kirchweger@salk.edu
858-357-7481
Salk Institute
Source:Eurekalert

Related medicine news :

1. Cancer-associated long noncoding RNA regulates pre-mRNA splicing
2. U of T researchers crack splicing code, solve a mystery underlying biological complexity
3. UCSF, UC Berkeley join forces to advance frontier of brain repair
4. Study reinforces link between obesity, high-fat meals and heart disease
5. Improved behavioral health needed to respond to rising number of suicides among US Armed Forces
6. Forces for cancer spread: Genomic instability and evolutionary selection
7. UCLA develops combat casualty care educational program for US armed forces
8. University of Colorado joins forces with major research affiliate
9. REPtrax and VendorClear Join Forces
10. B2Discovery: Entrepreneurs and researchers join forces to conquer cancer
11. OHSU joins forces with UO, Harvard to accelerate Fanconi anemia research
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/25/2016)... ... June 25, 2016 , ... On Friday, June 10, Van Mitchell, Secretary of ... award to iHire in recognition of their exemplary accomplishments in worksite health promotion. , ... Workplace Health & Wellness Symposium at the BWI Marriott in Linthicum Heights. iHire was ...
(Date:6/24/2016)... (PRWEB) , ... June 24, 2016 , ... Those who ... with these feelings, many turn to unhealthy avenues, such as drug or alcohol abuse, ... Marne, Michigan, has released tools for healthy coping following a traumatic event. , Trauma ...
(Date:6/24/2016)... ... June 24, 2016 , ... The Pulmonary Hypertension Association (PHA) ... will receive two significant new grants to support its work to advance research ... anniversary by recognizing patients, medical professionals and scientists for their work in fighting ...
(Date:6/24/2016)... ... June 24, 2016 , ... Comfort Keepers® of San ... Society and the Road To Recovery® program to drive cancer patients to and from ... adults to ensure the highest quality of life and ongoing independence. Getting to ...
(Date:6/24/2016)... ... June 24, 2016 , ... ... the Clinical Decision Making in Emergency Medicine conference in Ponte Vedra Beach, FL. ... articles published in Emergency Medicine Practice and Pediatric Emergency Medicine Practice. ...
Breaking Medicine News(10 mins):
(Date:6/24/2016)... June 24, 2016 The Academy of Managed ... recommendations that would allow biopharmaceutical companies to more ... that make formulary and coverage decisions, a move that ... new medicines. The recommendations address restrictions in ... on the drug label, a prohibition that hinders decision ...
(Date:6/24/2016)... --  Pulmatrix, Inc ., (NASDAQ: PULM ), ... today that it was added to the Russell Microcap ... set of U.S. and global equity indexes on June ... for Pulmatrix," said Chief Executive Officer Robert Clarke ... in developing drugs for crucial unmet medical needs, and ...
(Date:6/23/2016)... 23, 2016 Any dentist who has made an ... current process. Many of them do not even offer this ... and high laboratory costs involved. And those who ARE able ... such a high cost that the majority of today,s patients ... Parsa Zadeh , founder of Dental Evolutions Inc. and ...
Breaking Medicine Technology: