Sepsis – the leading cause of death in non-coronary ICU patients – may now
be brought under control
1. Sepsis, the severe inflammatory condition caused by bacterial infection, which
commonly afflicts patients in intensive care units (ICU), may soon be less lifethreatening.
Scientists from the Institute of Molecular and Cell Biology (IMCB) under
the Agency for Science, Technology and Research (A*STAR) have identified the
protein, WIP1, as the molecular “brake” to curb severe inflammation in the body.
2. In their landmark paper published in the May 2009 print issue of Nature Cell
Biology (NCB) and entitled, “WIP1 phosphatase is a negative regulator of NFκB
signalling”, the group of scientists led by IMCB principal investigator, Dr Vinay
Tergaonkar, highlighted the importance of WIP1 as an effective suppressor of
inflammation and explained how the body was able to cope with an excess of
inflammation brought on by the hyperactivation of NFκB1. “We have shown that
WIP1 plays a critical role in suppressing the activity of NFκB and keeping NFκB
levels within a safe range. In doing so, WIP1 minimises the extent of inflammatory
response that could lead to septic shock and subsequent death of patients,” said Dr
3. In their experiments to measure the level of inflammatory response in
laboratory mice, Dr Tergaonkar in collaboration with IMCB’s Dr Dmitry Bulavin,
discovered that the inflammatory response in mice lacking in WIP1 was higher than
that of the control group of mice with normal WIP1 levels. Correspondingly, the scientists
also found that the inflammatory response in mice with high WIP1 levels was suppressed.
Discovery that chronic inflammation may lead to cancer
4. In a separate research, another group of scientists also led by Dr Tergaonkar
found further evidence linking chronic inflammation to the development of cancers
such as that of the stomach and liver. Dr Tergaonkar and his colleagues discovered
that the kinase enzyme IκB kinase 2 (IKK2), which is known for causing inflammation
through the activation of NFκB, is also responsible for “ordering” the destruction of
the tumour suppressor protein p53. This discovery, published in the February 2009
print issue of the Proceedings of the National Academy of Sciences (PNAS) and
entitled, “Phosphorylation of p53 by IκB kinase 2 promotes its degradation by β-
TrCP”, provides fresh insight into how cells, which have become inflamed due to
exposure to high IKK2 activity, can become more susceptible to tumour development.
(The diagram of the molecular interactions is presented at the Annex.)
5. “Our recent discoveries have provided an explanation on the beneficial and
harmful effects of inflammation that have baffled scientists for years. While the
natural inflammatory response serves to help the body clear infection, excessive
inflammation, on the other hand, promotes cellular changes that lead to the
uncontrolled growth of cells that characterizes cancer and enables its spread. These
new insights involving NFκB, WIP1 and IKK2 are fostering new anti-inflammatory
therapeutic approaches to human ailments ranging from inflammation (like sepsis) to
cancer2,” added Dr Tergaonkar.
6. Said Prof Shen Han-Ming, an expert in cancer cell biology at the Yong Loo Lin
School of Medicine at the National University of Singapore, “I would like to
congratulate Dr Tergaonkar's group for their excellent work on nuclear transcriptional
factor NFκB. Taken together, the above-described work in Dr Tergaonkar's lab has
significantly advanced our understanding of the regulatory mechanisms of NFκB and
expanded the functional scope of NFκB. More importantly, such findings offer new
opportunities for modulation of the NFκB signalling pathway3 and for exploring new
therapeutic strategies in various human diseases such as cancer and sepsis.”
1 The NFκB protein complex is a well-established signalling molecule which
plays a key role in triggering inflammation.
2Dey A, Tergaonkar V, Lane DP. Nature Reviews Drug Discovery (2008), 7(12):1031.
Sethi G, and Tergaonkar V. Trends in Pharmacological Sciences (2009), in press.
3 Many previous studies, at IMCB and other labs, have identified NFκB
(nuclear factor-kappa B) as a key factor in both health and disease. Several anti-inflammatory
drugs on the market also target NFκB.
For more information, please contact:
Ms Wang Yunshi
Agency for Science, Technology and Research (A*STAR)
Tel: +65 6826 6443
Figure 1: Molecular interplay between the body’s inflammatory pathway and tumour
The research findings described in the press release can be found in the following
1. “WIP1 phosphatase is a negative regulator of NF-κB signalling”, Nature Cell
Biology, May 2009, 11(5), 659 – 666.
Authors: Chew J, Biswas S, Shreeram S, Humaidi M, Wong ET, Dhillion MK, Teo H,
Hazra A, Fang CC, López-Collazo E, Bulavin DV# and Tergaonkar VB*.
2. “Phosphorylation of p53 by IκB kinase 2 promotes its degradation by β-TrCP”,
Proceedings of the National Academy of Sciences (PNAS), Feb 2009, 106(8),
2629-2634. Authors: Xia Y, Padre RC, De Mendoza TH, Bottero V, Tergaonkar VB*, Verma IM.
Corresponding author: Dr Vinay Tergaonkar, email: email@example.com
# The work done at IMCB was also supported by the laboratory of Dr Dmitry Bulavin,
principal investigator at IMCB.
About the Institute of Molecular and Cell Biology (IMCB)
The Institute of Molecular and Cell Biology (IMCB) is a member of Singapore’s
Agency for Science, Technology and Research (A*STAR) and is funded through
A*STAR’s Biomedical Research Council BMRC). It is a world-class research
institute that focuses its activities on six major fields: Cell Biology, Developmental
Biology, Structural Biology, Infectious Diseases, Cancer Biology and Translational
Research, with core strengths in cell cycling, cell signalling, cell death, cell motility
and protein trafficking. Its recent achievements include leading an international
consortium that successfully sequenced the entire pufferfish (Fugu) genome. The
IMCB was awarded the Nikkei Prize 2000 for Technological Innovation in recognition
of its growth into a leading international research centre and its collaboration with
industry and research institutes worldwide. Established in 1987, the Institute
currently has 35 independent research groups with more than 400 staff members.
For more information, please visit: www.imcb.a-star.edu.sg
About the Agency for Science, Technology and Research
The Agency for Science, Technology and Research, or A*STAR, is Singapore's lead
agency for fostering world-class scientific research and talent for a vibrant
knowledge-based Singapore. A*STAR actively nurtures public sector research and
development in Biomedical Sciences, Physical Sciences and Engineering, with a
particular focus on fields essential to Singapore's manufacturing industry and new
growth industries. It oversees 14 research institutes and supports extramural
research with the universities, hospital research centres and other local and
international partners. At the heart of this knowledge-intensive work is human capital.
Top local and international scientific talent drive knowledge creation at A*STAR
research institutes. The Agency also sends scholars for undergraduate, graduate
and post-doctoral training in the best universities, a reflection of the high priority
A*STAR places on nurturing the next generation of scientific talent.
For more information, please visit: http://www.a-star.edu.sg