Navigation Links
Loss of tumor-suppressor and DNA-maintenance proteins causes tissue demise

PHILADELPHIA - A study published in the October issue of Nature Genetics demonstrates that loss of the tumor-suppressor protein p53, coupled with elimination of the DNA-maintenance protein ATR, severely disrupts tissue maintenance in mice. As a result, tissues deteriorate rapidly, which is generally fatal in these animals. In addition, the study provides supportive evidence for the use of inhibitors of ATR in cancer therapy.

Essentially, says senior author Eric Brown, PhD, Assistant Professor of Cancer Biology at the University of Pennsylvania School of Medicine, the findings highlight the fact that day-to-day maintenance required to keep proliferative tissues like skin and intestines functional is about more than just regeneration, a stem cell-based process that forms the basis of tissue renewal. It's also about housekeeping, the clearing away of damaged cells.

Whereas loss of ATR causes DNA damage, the job of p53 is to monitor cells for such damage and either stimulate the early demise of such cells or prevent their replication, the housekeeping part of the equation. The findings indicate that as messy as things can become in the absence of a DNA maintenance protein like ATR, failing to remove resulting damaged cells by also deleting p53, is worse. "Because the persistence of damaged cells in the absence of p53 prevents appropriate tissue renewal, these and other studies have underscored the importance not only of maintaining competent stem cells, but also of eliminating what gets in the way of regeneration," explains Brown.

"An analogy to our findings is what happens to trees during the changing seasons," says Brown. "In springtime, leaves are new and undamaged. But as the summer wears on, the effects of various influences - insects, drought, and disease - cause them to lose the pristine qualities they once had. However, the subsequent fall of these leaves presents a unique opportunity for regeneration later on, a chance to rejuvenate from anew without pre-existing obstacles. Similarly, by suppressing the accumulation of damaged cells in tissues, p53 permits more efficient tissue renewal when ATR is deleted."

Cells without ATR that remain uncleared may be block tissue regeneration either by effectively refusing to relinquish space to undamaged cells, or by secreting signals that halt regeneration until they have been removed.

These results came as something of a surprise, says Brown. Previous studies pairing DNA-repair mutations with p53 mutations always led to a partial rescue of the DNA repair mutation "We think this happens because p53 loss helps cells with just a little DNA damage to continue to contribute to the tissue" says Brown. So at a minimum, the team expected nothing to happen.

"But we got the opposite result: Absence of p53 did not rescue the tissue degeneration caused by ATR loss, it made it much worse. This result suggested that allowing mutant cells without ATR to persist is more harmful to tissues than eliminating them in the first place." Brown speculates that could be because the ATR mutation produces much more damage than most other DNA-repair defects.

According to Brown, their findings and those of other laboratories also reinforce the potential of a new therapeutic for cancer. That's because, among their other discoveries, the team noticed that cells missing both ATR and p53 have more DNA damage than those missing either gene alone. As a large fraction of human cancers have p53 mutations, he says, "p53-deficient tumors might be especially susceptible to ATR inhibition." Indeed, clinical trials already are underway involving an ATR partner protein called Chk1. "Our study provides supportive evidence for the potential use of ATR/Chk1 inhibitors in cancer therapy," says Brown


Contact: Karen Kreeger
University of Pennsylvania School of Medicine

Related medicine news :

1. Cold Spring Harbor science teams identify 13 new tumor-suppressor genes in liver cancer
2. Oncoproteins double-team and destroy vital tumor-suppressor
3. M. D. Anderson researchers identify tumor-suppressor gene for lung cancer
4. New findings about brain proteins suggest possible way to fight Alzheimers
5. Replication at DNA damage sites highlights Fanconi anemia and breast cancer proteins
6. New Antibiotics May Target Cancer-Causing Proteins
7. Brain Imaging (MRI/PET) and Measurements of Proteins in Spinal Fluid May Improve Alzheimers Prediction and Diagnosis
8. Researchers identify key proteins needed for ovulation
9. Scripps research scientists model 3D structures of proteins that control human clock
10. Bioengineered proteins: Trial confirms new way to tackle cancer
11. Motor proteins may be vehicles for drug delivery
Post Your Comments:
Related Image:
Loss of tumor-suppressor and DNA-maintenance proteins causes tissue demise
(Date:11/29/2015)... (PRWEB) , ... November 29, 2015 , ... While conventional ... kneeling or provide ready access to exercise weights. Fortunately, an inventor from Uniontown, Pa., ... THE TOMMY WALKER to enhance the benefits of a standard walker to improve the ...
(Date:11/29/2015)... ... November 29, 2015 , ... Key Housing, a top-rated corporate ... their December, 2015, featured apartment community: Epic. In showcasing this featured apartment community in ... tight Bay Area rental market to efficiently find housing suitable to their needs by ...
(Date:11/28/2015)... ... 28, 2015 , ... Beginning November 30th at 6:00 a.m. EST until 11:59 p.m. EST, ... possible savings of up to 20% off orders $80 or more to free gifts with ... few hours. , As a competitive e-commerce website for skin care and cosmetic needs, customers ...
(Date:11/27/2015)... CA (PRWEB) , ... November 27, 2015 , ... According ... carried out by the University of Toronto and the University of British Columbia suggested ... hospitalizations for head injuries. The article explains that part of the reason for the ...
(Date:11/27/2015)... (PRWEB) , ... November 27, 2015 , ... ... a safe and convenient way to dispense prescription medications at home, so he ... effective way to monitor and dispense prescription medications. In doing so, it could ...
Breaking Medicine News(10 mins):
(Date:11/30/2015)... Sectra (STO: SECT B) ... into a multi-year agreement to provide Breast Imaging PACS ... Breast Care to increase collaboration with sub-specialists around the ... --> Sectra (STO: SECT B) ... into a multi-year agreement to provide Breast Imaging PACS ...
(Date:11/29/2015)... AMSTERDAM , Nov. 29, 2015  Strengthening its ... (NYSE: PHG, AEX: PHIA) today announced IntelliSpace Portal ... sharing, analytics and visualization platform that helps radiologists detect, ... the 2015 Radiological Society of North America Annual ... , IntelliSpace Portal 8.0 helps address the changing demands ...
(Date:11/29/2015)... Nov. 29, 2015   Royal Philips  (NYSE: PHG, ... solutions at the 2015 Radiological Society of North America ... McCormick Place in Chicago . Visitors ... the company,s broad portfolio of integrated Diagnostic Imaging, Clinical ... increase clinical performance, improve workflow and create a superior ...
Breaking Medicine Technology: