Vinay TERGAONKAR

NFkB Signaling in Human Ailments

Profile

Vinay TERGAONKAR
Lab Location: #3-17   Email: vinayt@imcb.a-star.edu.sg   Tel: 65869836

Vinay Tergaonkar obtained his Ph.D in 2001. During his graduate studies he was awarded an international cancer society (UICC) fellowship for collaborative research at Tufts University, Boston, USA. He has been a fellow (2001-2004) and a special fellow (2004-present) of the Leukemia and Lymphoma Society of America and conducted his postdoctoral studies at the Salk Institute for Biological Studies, La Jolla, California. He joined IMCB in late 2005 as Principal Investigator and became a Senior Principal Investigator in 2010 and Research Director in 2015. He is also a Professor at the school of Medicine, National University of Singapore.

He also holds adjunct appointments at 1) Cancer Science Institute, Singapore, 2) Singapore Eye Research Institute and a visiting position at CCB/UniSA, Australia. He has been invited to speak at various international venues and meetings such as the Barossa and Hunter valley meetings in Australia, Genes and Cancer meeting in UK, The Argentine Pharmacological society meeting in Buenos Aires, Aichi and Japanese Cancer Society meetings in Japan and the Keystone Symposia. He serves on Editorial Boards of 1) Molecular and Cellular Biology (American Society for Microbiology), 2) Biochemical Journal (Portland Press) 3) Critical Reviews in Oncology/Hematology (Elsevier Press), 4) BMC Research Notes (Biomed Central) and 5) Telomeres and Telomerase. Work from his laboratories has led to international recognition, including the British council development award (2014) and the Premier's fellowship from Government of South Australia (2015).

Research

Inflammation, Cancer epigenetics and Metabolism

Inflammation involving the innate and adaptive immune systems is a normal response to infection. However, it is now known that when allowed to continue unchecked, chronic inflammation is a key underlying cause for the development of autoimmune disorders, neurodegenerative diseases, metabolic syndromes such as diabetes and cancer. Our lab studies a transcription factor called NFkB which is a master regulator of inflammation. Indeed deregulated activity of NFkB precedes and is causally linked to chronic inflammation and the development of several human ailments including metabolic syndromes and cancers. However, given that NFkB signaling is also essential for many housekeeping cellular and developmental events in normal human beings, simply blocking NFkB B to curb inflammation is not an option. Hence deciphering the regulation of NFkB signaling is crucial to understanding the mechanism and role of uncontrolled/unwanted NFkB activity seen in human ailments and in developing better and safer anti-inflammatory drug. We are focusing and our efforts to identify targets that will help develop drugs which will block NFkB /inflammation more selectively and not generically and hence may have less side effects.

a) Mechanisms that initiate and maintain chronic inflammation in cance

Chronic Inflammation such as that triggered by infectious agents is a key driver of human cancers. Two sets of Nobel prizes were awarded in last 7 years (a) to discovery of Helicobacter as cause of gastric cancers (2005) and (b) to the discovery of Human Papilloma Virus as a causative agent for cervical cancer (2008). However, even in cancers where these infectious agents are not present, inflammation is now known as a key driver. That is why people on asprin (an anti-inflammatory drug) have significantly lower risk of some cancers and on the other hand, obese individual (who have chronic inflammation) without infectious agents have more cancers of certain kind. But what activates and sustains chronic inflammation in cancers is not understood at all. Another hallmark of all human cancers is that cancer cells divide endlessly and for this they need an enzyme called telomerase (discovery of which received Nobel prize in 2009). But many pieces of evidence suggest that telomerase enzyme has other roles apart from making cells divide endlessly. We find time that telomerase enzyme, is the key missing link that in addition to its role in cell division also kick starts and maintains chronic inflammation in cancers. Our findings have immense therapeutic implications and we are developing drugs blocking this enzyme and find that in experiental settings such thearpies are showing promising results in blocking cancer inflammation and cancer cell division.

b) New epigenetic controls of inflammation

Deciphering the regulation of critical regulators of inflammation such as NFkB is crucial to understanding the mechanism and role of constitutive NFkB activity seen in human ailments. Given that over 200 physiological stimuli activate NFkB, which in turn regulates an equally large number of genes, understanding how specificity is generated in such a pleiotropic pathway is also a major challenge. Using large-scale functional genomics and proteomic approaches, our group has identified several novel modifiers of NFkB activity. Using genetic and epigenetic approaches, we are keen to decipher the mechanisms by which these novel regulators modulate NFkB and hence chronic inflammation in human aimments.

c) Mechanisms that regulate chronic inflammation in metabolic syndrome

Type 2 diabetes (T2D) and one of its major risk factors, obesity are pandemic problem. Inherent genetic predispositions in combination with inappropriate diet and sedentary lifestyle contribute to the pathogenesis of these disorders. A better understanding of inflammatory signaling is critical for development of therapeutic strategies towards T2DM and obesity. As part of a directed screen to identify molecules that respond to dietary and inflammatory cues in adipose tissue during development of obesity and insulin resistance, we have identified several signaling molecules. Of particular mention is a protein called NUCKS (Nuclear Ubiquitous Casein and cyclin-dependent Kinase Substrate), expression of which is inversely correlated with body mass index in humans and body fat in mice. Ablation of NUCKS results in weight gain, increased body fat accumulation, glucose intolerance and insulin resistance. NUCKS is a key chromatin modifier and transcriptional regulator of a number of signaling genes. We are characterizing the roles of proteins like NUCKS in metabolic syndromes.

Prospective Graduate Students:

SINGA fellowships:

Please look at Astar scholarships webpage.

The link is here:
https://www.a-star.edu.sg/singa-award/

Prospective Interns:

The Singapore International Pre-Graduate Award (SIPGA) supports short-term research attachments for international students at A*STAR. It provides a unique opportunity for top overseas students to experience the vibrant scientific environment in A*STAR Research Institutes and Consortia. Students will be able to work with distinguished and world- renowned researchers in A*STAR labs. This award will normally be for students in the later years of a Bachelor or Master level program. Students considering PhD studies in A*STAR are encouraged to apply.

The link is here:
http://www.a-star.edu.sg/Awards-Scholarship/Scholarships-Attachments/For-Undergraduate-Studies/Singapore-International-Pre-Graduate-Award.aspx

Staff

Department: Vinay TERGAONKAR

Name: Semih Can AKINCILAR

Designation: Research Fellow

Email: semiha@imcb.a-star.edu.sg


Name: Sultan Abda NEJA

Designation: SINGA Student

Email: nejasa@student.imcb.a-star.edu.sg


Name: Mert Burak OZTURK

Designation: SINGA Student

Email: ozturkmb@student.imcb.a-star.edu.sg


Name: Qi Ling ZHOU

Designation: Student(NUS)

Email: qlzhou@imcb.a-star.edu.sg


Name: Stephanie Ana CONOS

Designation: Research Fellow

Email: conossa@imcb.a-star.edu.sg


Name: Erica Shiyi WONG

Designation: Research Officer

Email: sywong@imcb.a-star.edu.sg


Name: Esther Meimei LUO

Designation: Scientific Manager

Email: mmluo@imcb.a-star.edu.sg


Name: Qian LI

Designation: Research Fellow

Email: qli@imcb.a-star.edu.sg


Name: Joanna Sok Hui GOH

Designation: Research Officer

Email: gohsh@imcb.a-star.edu.sg


Name: Lele WU

Designation: Research Fellow

Email: wull@imcb.a-star.edu.sg


Name: Zahra Eslami SAMARIN

Designation: Internship

Email: internzaes@imcb.a-star.edu.sg


Name: Shin Yong JAE

Designation: Collaborator

Email: jaesy@imcb.a-star.edu.sg


Name: Swizzle R. Y. KO

Designation: Collaborator

Email: kosry@imcb.a-star.edu.sg


Name: Miseol SON

Designation: Research Officer

Email: sonm@imcb.a-star.edu.sg


Name: Kyaw Ze Ya MAUNG

Designation: Research Fellow

Email: maungkzy@imcb.a-star.edu.sg


Name: Ambarnil GHOSH

Designation: Research Fellow

Email: ambarnilg@imcb.a-star.edu.sg


Name: Thamil Selvam VAIYAPURI

Designation: Rsearch Fellow

Email: thamilsv@imcb.a-star.edu.sg


Name: Dhakshayini D/O K. CHANTHIRA MORGAN

Designation: Research Officer

Email: dhakshayini@imcb.a-star.edu.sg


Name: Chen Li CHEW

Designation: Research Fellow

Email: clchew@imcb.a-star.edu.sg


Name: Kerem FIDAN

Designation: PhD Student (SINGA)

Email: keremf@student.imcb.a-star.edu.sg


Name: Yinghui LI

Designation: Principal Investigator

Email: liyh@imcb.a-star.edu.sg


Name: Eun Myoung SHIN

Designation: Collaborator

Email: csieunm@nus.edu.sg


Name: Sook Yee LEE

Designation: Research Fellow

Email: sylee@imcb.a-star.edu.sg


Name: Hiu Yan LAM

Designation: PhD Student (SINGA)

Email: hylam@student.imcb.a-star.edu.sg


Name: Vinh Thang HUYNH

Designation: Student (SINGA)

Email: vhthang@student.imcb.a-star.edu.sg


Publications

Publications 2006-2009

Akıncılar SC, Khattar E, Boon PL, Unal B, Fullwood MJ, Tergaonkar V.
Long-Range Chromatin Interactions Drive Mutant TERT Promoter Activation.
Cancer Discovery. 2016 Nov;6(11):1276-1291.

Khattar E, Kumar P, Liu CY, Akıncılar SC, Raju A, Lakshmanan M, Maury JJ, Qiang Y, Li S, Tan EY, Hui KM, Shi M, Loh YH, Tergaonkar V.
Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression.
Journal of Clinical Investigation. 2016 Oct 3;126(10):4045-4060. doi: 10.1172/JCI86042.

Li Y, Zhou QL, Sun W, Chandrasekharan P, Cheng HS, Ying Z, Lakshmanan M, Raju A, Tenen DG, Cheng SY, Chuang KH, Li J, Prabhakar S, Li M, Tergaonkar V.
Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation. 
Nature Cell Biology (article).
2015 Oct;17(10):1327-38.

Cheryl M Koh, Ekta Khattar, Shi Chi Leow, Chia Yi Liu, Julius Muller, Wei Xia Ang, Yinghui Li, Guido Franzoso, Shang Li, Ernesto Guccione and Vinay Tergaonkar. (2015).
Telomerase regulates Myc dependent Oncogenesis independent of its reverse transcriptase activity.
Journal of Clinical Investigation. In Press.

Shin, E.M,. Lee, M., Goh , J., Ong, H., Ong, CW., Mendoz, E., Sun, W., Kong, X., Tan, T., Salto-Tellez, M., Putti, TC., Zhu, T., Thiery, J.P., Miyamoto, S., Kumar, A.P.,  Tergaonkar, V. (2014).
DP103 defines the metastatic potential of human breast cancers. 
Journal of Clinical Investigation.
24(9):3807-24.

Ghosh A, Saginc G, Leow SC, Khattar E, Shin EM, Yan TD, Wong M, Zhang Z, Li G, Sung WK, Zhou J, Chng WJ, Li S, Liu E, Tergaonkar V. (2012).
Telomerase directly regulates NF-κB-dependent transcription.
Nature Cell Biology (article) 2012 Dec;14(12):1270-81. doi: 10.1038/ncb2621. Epub 2012 Nov 18.

Zhao-Hui Wu, Ee Tsin Wong, Yuling Shi, Zhijian Chen, Shigeki Miyamoto and Vinay Tergaonkar. (2010).
ATM-dependent ELKS ubiquitination coordinates IKK activation in response to genotoxic stress.
Molecular Cell. ;40(1):75-86.

Ghosh,  and VInay Tergaonkar. (2010).
Telomeres and inflammation: Rap1 joins the ends?
Cell Cycle. 9(19):3834-5.

Hsiangling Teo, Sourav Ghosh , Hendrik Luesch , Ee Tsin Wong, Arkasubhra Ghosh, Najib Malik, Anthony Orth, Paul de Jesus, Anthony S Perry, Jeffrey D. Oliver, Nhan L. Tran, Lisa J. Speiser, Enrique Saez,  Peter Schultz, Sumit Chanda, Inder M Verma and Vinay Tergaonkar. (2010).
Telomere independent Rap1 is an IKK-adaptor and regulates NFkB- dependent gene expression.
Nature Cell Biology (article). 12(8):758-67.
Covered by local and international press.

Tergaonkar V. (2009).
p53 and NFkappaB: fresh breath in the cross talk.
Cell Research. 19 (12), 1313-5.

Susila A, Chan H, Loh AX, Phang HQ, Wong ET, Tergaonkar V, Koh CG. (2010).
The POPX2 phosphatase regulates cancer cell motility and invasiveness.
Cell Cycle. 9(1), 179-87.

Sethi G, Tergaonkar V. (2009).
Potential pharmacological control of the NF-kappaB pathway.
Trends in Pharmacological Sciences. 30(6), 313-21.

Chew J, Biswas S, Shreeram S, Humaidi M, Wong ET, Dhillion MK, Teo H, Hazra A, Fang CC, López-Collazo E, Bulavin DV, Tergaonkar V. (2009).
WIP1 phosphatase is a negative regulator of NF-kappaB signalling.
Nature Cell Biology. 11(5), 659-66.
Covered by local and international press.

Shen HM, Tergaonkar V. (2009).
NFkappaB signaling in carcinogenesis and as a potential molecular target for cancer therapy.
Apoptosis. 14(4), 348-63.

Wong ET, Tergaonkar V. (2009).
Roles of NF-kappaB in health and disease: mechanisms and therapeutic potential. Clinical Science (Lond). 116(6), 451-65.

Xia Y, Padre RC, De Mendoza TH, Bottero V, Tergaonkar VB*, Verma IM. (2009). Phosphorylation of p53 by IkappaB kinase 2 promotes its degradation by beta-TrCP. Proc Natl Acad Sci U S A. 106(8), 2629-34. * Corresponding Author

Singh K, Sinha S, Malonia SK, Bist P, Tergaonkar V, Chattopadhyay S. (2009).
Tumor suppressor SMAR1 represses IkappaBalpha expression and inhibits p65 transactivation through matrix attachment regions.
J Biol Chem. 284(2), 1267-78.

Dey A, Tergaonkar V*, Lane DP. (2008).
Double-edged swords as cancer therapeutics: simultaneously targeting p53 and NF-kappaB pathways.
Nature Reviews Drug Discovery. 7(12), 1031-40. * Corresponding Author

Dey A, Wong E, Kua N, Teo HL, Tergaonkar V*, Lane D. (2008).
Hexamethylene bisacetamide (HMBA) simultaneously targets AKT and MAPK pathway and represses NF kappaB activity: implications for cancer therapy.
Cell Cycle. 7(23), 3759-67.
* Corresponding Author

Lee KG, Xu S, Wong ET, Tergaonkar V, Lam KP. (2008).
Bruton's tyrosine kinase separately regulates NFkappaB p65RelA activation and cytokine interleukin (IL)-10/IL-12 production in TLR9-stimulated B Cells.
J Biol Chem. 283(17), 11189-98.

Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, Brink R, Leverkus M,
Tergaonkar V, Schneider P, Callus BA, Koentgen F, Vaux DL, Silke J. (2007).
 IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.
Cell. 131(4), 682-93.

Dey A, Wong ET, Cheok CF, Tergaonkar V*, Lane DP. (2008).
R-Roscovitine simultaneously targets both the p53 and NF-kappaB pathways and causes potentiation of apoptosis: implications in cancer therapy.
Cell Death Differ. 15(2), 263-73. *Corresponding Author

Irelan JT, Murphy TJ, DeJesus PD, Teo H, Xu D, Gomez-Ferreria MA, Zhou Y, Miraglia LJ, Rines DR, Verma IM, Sharp DJ, Tergaonkar V, Chanda SK. (2007).
A role for IkappaB kinase 2 in bipolar spindle assembly.
Proc Natl Acad Sci U S A. 104(43), 16940-5.

Ang HL, Tergaonkar V. (2007).
Notch and NFkappaB signaling pathways: Do they collaborate in normal vertebrate brain development and function? Notch and NFkappaB signaling pathways: Do they collaborate in normal vertebrate brain development and function?
Bioessays. 29(10), 1039-47.

Dey A, Wong ET, Bist P, Tergaonkar V, Lane DP. (2007).
Nutlin-3 inhibits the NFkappaB pathway in a p53-dependent manner: implications in lung cancer therapy.
Cell Cycle. 6(17), 2178-85.

Biswas SK, Bist P, Dhillon MK, Kajiji T, Del Fresno C, Yamamoto M, Lopez-Collazo E, Akira S, Tergaonkar V. (2007).
Role for MyD88-independent, TRIF pathway in lipid A/TLR4-induced endotoxin tolerance.
Journal of Immunology. 179(6), 4083-92.

Biswas SK, Tergaonkar V. (2007).
Myeloid differentiation factor 88-independent Toll-like receptor pathway: Sustaining inflammation or promoting tolerance?
Int J Biochem Cell Biol. 39(9), 1582-92.

Tergaonkar V*, Perkins ND. (2007).
p53 and NF-kappaB crosstalk: IKKalpha tips the balance.
Molecular Cell. 26(2), 158-9. *Corresponding author.

Basak S, Kim H, Kearns JD, Tergaonkar V, O'Dea E, Werner SL, Benedict CA, Ware CF, Ghosh G, Verma IM, Hoffmann A. (2007).
A fourth IkappaB protein within the NF-kappaB signaling module.
Cell. 128(2), 369-81.

Ghosh S, Tergaonkar V*, Rothlin CV, Correa RG, Bottero V, Bist P, Verma IM, Hunter T. (2006).
Essential role of tuberous sclerosis genes TSC1 and TSC2 in NF-kappaB activation and cell survival.
Cancer Cell. 10(3), 215-26. *Co-first author

Tergaonkar V. (2006).
NFkappaB pathway: a good signaling paradigm and therapeutic target.
Int J Biochem Cell Biol. 38(10), 1647-53.

Publications before joining IMCB
Muotri AR, Bottero V, Tergaonkar V, Correa RG. (2006).
UV-mediated NF-kappaB activation is abolished in deficient XPC/D primary fibroblasts
Cell Cycle. 5(10), 1085-9.

Tergaonkar, V., Correa, R.G., Ikawa, M. and Verma, I.M. (2005).
Distinct roles of IkappaB proteins in regulating constitutive NF-kappaB activity.
Nature Cell Biology. 7, 921-923.

Correa, R.G., Matsui, T*., Tergaonkar, V*., Rodriguez-Esteban C, Izpisua-Belmonte, J.C, and Verma, I.M. (2005)
Zebrafish IkappaB kinase 1 negatively regulates NF-kappaB activity.
Current Biology. 15, 1291-1295. *Equal contribution

Correa, R., Tergaonkar, V., Ng, J. K., Izpisua Belmonte, J-C. and Verma I.M. (2004). Characterization of NF-kappa B/I kappa B proteins in zebra fish and their involvement in notochord development.
Mol Cell Biol. 24, 5257-5268.

Chakrabarti, O., Veeraraghavalu, K., Tergaonkar, V., Liu, Y., Androphy, E.J., Stanley, M.A. and Krishna, S. (2004).
Human papillomavirus type 16 E6 amino acid 83 variants enhance E6-mediated MAPK signaling and differentially regulate tumorigenesis by notch signaling and oncogenic Ras.
Journal of Virology. 78, 5934-5945.

Tiscornia, G., Tergaonkar, V., Galimi, F. and Verma IM. (2004).
CRE recombinase-inducible RNA interference mediated by lentiviral vectors.
Proc Natl Acad Sci USA. 101, 7347-51.

Tergaonkar, V., Bottero V., Ikawa, M., Li, Q. and Verma, I.M. (2003).
IKK independent IkBa degradation pathway: functional NFkB activity and implications for cancer therapy.
Mol Cell Biol.  23, 8070-8083.
Selected as one of the six best papers of the month by American Society for Microbiology (ASM).

Tergaonkar, V., Pando, M., Vafa, O., Wahl, G. and Verma I.M. (2002).
p53 stabilization is decreased upon NFkB activation: a role for NFkB in acquisition of resistance to chemotherapy.
Cancer Cell. 1, 493-503.

Ikawa, M., Tergaonkar, V., Ogura, A., Ogonuki, N., Inoue, K. and Verma, I.M. (2002). Restoration of spermatogenesis by lentiviral gene transfer: Offspring from infertile mice.
Proc Natl Acad Sci USA
. 99, 7524-7529.
Cited by CNN, ABC, Reuters and other news agencies around the world on 28th May 2002.

Liu, Y., Tergaonkar, V., Krishna, S. and Androphy, E. (1999).
Human papillomavirus type 16-enhanced susceptibility of L929 cells to tumour necrosis factor correlates with increased production of reactive oxygen species.
J Biol Chem. 274, 24819-24827.

Mythily, D.V., Krishna, S. and Tergaonkar, V. (1999).
Pleiotropic effects of human papillomavirus type 16 E6 oncogene expression in human epithelial cell lines.
J Gen Virol. 80, 1701-1713.

Tergaonkar, V., Mythily, D.V. and Krishna, S. (1997).
Cytokeratin patterns of expression in human epithelial cell lines correlate with transcriptional activity of the HPV16 URR.
J Gen Virol. 78, 2601-2607.

Book Chapters and Proceedings

Muthu K Shamugam, Vinay Tergaonkar, and Gautam Sethi. Inflammation in Cancer Development. (2010).
Taylor and Francis Group, LLC.,   entitled “Inflammation, Life Style and Chronic Diseases: The Silent Link.

Withoff,  S., Tergaonkar V and Verma IM. (2006).
Regulating the master regulator NFkB: From Natural strategies to rationally designed superdrugs.
Transcription Factor NF
kB. Book commemorating 20 years of NF-kB. Preface David Baltimore.
Cold Spring Harbor Press.

Tergaonkar, V., Li, Q., and Verma, I.M. (2005)
Inhibitors of NFkB activity: Tools for treatment of human ailments. NFkB/Rel
Transcription Factor Family.
ISBN: 1-58706-270-4.
Landes Bioscience and Springer.

Krishna, S., Sayal, R., Mythily, D.V., Tergaonkar, V. and Rangarajan, A. (1999).
The role of the Notch pathway in viral induced tumors. Proceedings of the 2nd ICGEB-UCI Virology Symposium Eds S. Jameel and E.K. Wagner, OUP and IBH, pp1023-1030.

Krishna, S., Shashidhara, L.S., Deshpande, N., Daniel, B. and Tergaonkar, V. (1996).
In vivo approaches to studying human papillomaviruses. Proceedings of the first International Center for Genetic Engineering and Biotechnology (ICGEB)-University of California Irvine (UCI) Virology Symposium. Eds S. Jameel and E.K. Wagner, OUP and IBH, pp 223-230.

Tergaonkar, V., Vallikad, E. and Krishna, S. (1994). 
Analysis of HPV16 E2 gene expression in the progression of cervical cancers.
Proceedings of the XVI
International Cancer Congress,  Monduzzi Editore 3, 2271-2275.

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