NCCS scientists discovers pathway regulating the abundance of a protein that confers resistance to chemotherapeutic regimens in cancer cells
Wednesday, 17 Feb 2010
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Genotoxic Drugs in chemotherapy regimens is effective in eliminating DNp73 |
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C-Jun is critical in improving the tumour-suppressor functions of TAp73 and at the same time
eliminates the proliferation of DNp73 in cancer cells |
Singapore, 17 Feb 2010 –
Scientists at the National Cancer Centre Singapore have found the way to inhibit DNp73, a protein that is present in cancerous cells contributing to their growth and conferring resistance to therapy. The study has helped to shed light on how DNp73 over-expressing cancers can be made sensitive to chemotherapeutic regimes.
The scientific team led by NCCS Prof Kanaga Sabapathy, the Principal Investigator in the Laboratory of Carcinogenesis, which carried out the research on the p73 protein. Earlier findings have suggested p73, which is a close relative of the famous tumor suppressor p53, exists in two forms:
(a) TAp73 which has tumour suppressing functions that leads to programmed cell death and hence, inhibition of cellular growth; and
(b) DNp73 – a similar but shorter version which lacks the trans-activation domain prevalent in TAp73, and has oncogenic properties and hence promotes growth of cancerous cells.
Prof Sabapathy was also the PI who showed that the tumour suppressive TAp73 form is stabilized and activated by similar signals that reduce DNp73 levels.
When both forms are equally over-expressed in cancer cells, DNp73 becomes the dominant protein of the two and has the tendency to eradicate the tumour suppressing functions of TAp73 or p53.
In his research, Prof Sabapathy and his team found that the efficacy of TAp73 as a tumour suppressor can be enhanced in c-Jun, a protein that functions as a transcription factor. When genotoxic stress is introduced onto cells via chemotherapeutic regimes, c-Jun is activated to up-regulate TAp73 into performing its functions and at the same time
down-regulates DNp73.
In his latest publication “The anti-apoptotic Delta Np73 is degraded in a c-Jun-dependent manner upon genotoxic stress through the antizyme-mediated pathway”, Prof Sabapathy documented the key and novel findings of his study:
(a) degradation of DNp73 occurs when stress is induced via the proteasome and that which is independent of ubiquitination – the normal process by which proteins are degraded;
(b) c-Jun is required for this process after exposure to genotoxic stress;
(c) DNp73 is destabilized by the novel antizyme pathway;
(d) c-Jun is critical and necessary to regulate the antizyme pathway leading to DNp73 degradation.
The team was investigating on how DNp73 levels are regulated, so as to understand the mechanisms which can be utilized to modulate its expression in cancer cells. In doing so, they discovered that c-Jun, a protein that is induced by a variety of stress signals, is sufficient to cause the degradation of DNp73. Because c-Jun is a protein not known to play a direct role in regulating protein abundance, they searched for molecules that were regulated by c-Jun that can do the job. In so doing, they discovered that Antizyme (a class of protein that is involved in the non-classical pathway of ubiquitin-independent protein degradation via the proteasome), was capable of degrading DNp73. To ascertain if the processed version of Antizyme (Az1) was inducible by genotoxic stresses, the team used an antibody that only recognizes Az1 and added Putrescine, a polyamine family member that is the natural inducer of Antizyme (Az1). The result suggested that stress signals induced Az1, similar to polyamines, and polyamine addition was also sufficient for DNp73 degradation. These processes were found to be dependent on the presence of c-Jun, leading the team to conclude that c-Jun and the polyamine pathway are involved in the control of Az1 processing, thereby regulating the abundance of DNp73 upon
exposure to genotoxic stresses.
The publication has been accepted by the Proceedings of the National Academy of Sciences of the United States of America (PNAS), one of the most cited multidisciplinary scientific serials that publish cutting-edge research reports.
To view the paper, please see attachment.
Prof Kanaga Sabapathy will be available for media interview. For more information, please contact:
Ms Veronica Lee
Senior Executive, Corporate Communications
Tel: 6236 9429 / 9450 4017
Email: Veronica.Lee.H.E@nccs.com.sg
Ms Carol Ang
Executive, Corporate Communications
Tel: 6236 9424 / 9845 5354
Email: Carol.Ang.S.Y@nccs.com.sg
Mr Joshua Tan
Corporate Communications Officer
Tel: 6236 9462
Email: Joshua.Tan@nccs.com.sg
About NCCS
The National Cancer Centre Singapore (NCCS) is the premier cancer research and treatment facility in Singapore and in the region. It was established in 1997 and sees about 68 per cent of the public sector medical oncology cases and about 65 per cent of radiation oncology cases. NCCS not only houses the most number of oncologists in Singapore but is also equipped with the largest number of equipment to provide the latest radiation oncology care in Singapore.
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