Apoptosis & Cancer Biology Programme

Overview:

The Apoptosis and Cancer Biology Program is a multidisciplinary programme designed to provide a broad understanding of the cells' growth regulatory machinery and the mechanism(s) involved in oncogenesis. The focus of the program is to provide an environment that stimulates excellence in scientific thought and reasoning while simultaneously providing exposure to the major fields of study relevant to cancer biology. Research and training by the members of the programme are broadly focused on signal transduction, reactive oxygen species, regulation of the death signal, cell cycle control, gene regulation, oncogene and tumor suppressor action, drug resistance and antitumor pharmacology. Students participate in laboratory-based research, as well as in a tumor biology curriculum that integrates current concepts in cell growth control with the natural history of human tumors. 

Staff Involved:

Prof Shazib Pervaiz (Programme Coordinator)
Professor Peter Hwang
A/Prof Hooi Shing Chuan
A/Prof Lee Chee Wee
A/Prof M. Prakash Hande
Dr Shali Shen
Dr Celestial Yap 

Principal Investigator: A/Prof Hooi Shing Chuan


Role of histone deacetylases in cancer: Histone acetylation is an important epigenetic mechanism in the control of gene transcription. Acetylation status of histones and key regulators of the cell cycle has recently been shown to be important in cancer development. The laboratory is interested in understanding the role of histone deacetylases in the development of colorectal cancer. Also, in collaboration with Lynk Biotechnologies, we are hoping to come up with novel, more potent and specific histone deacetylase inhibitors.

Principal Investigator: A/Prof Hooi Shing Chuan


Genes involved in metastatic cancer: We have established a highly metastatic colorectal cancer cell line from a parental poorly metastatic line. The candidate genes and proteins involved in the metastatic process will be identified using microarray and proteomics. The involvement of these genes and proteins will be validated both in vitro and in vivo.

Principal Investigator: A/Prof Hooi Shing Chuan


Regulation of apoptosis by reactive oxygen species: An increase in the intracellular generation of reactive oxygen species (ROS) such as superoxide (O2.-) and hydrogen peroxide (H2O2) or a defect in the anti-oxidant defense system renders the cells oxidatively stressed, a state harmful for cell survival. However, recent evidence has added a newer dimension to the effects of elevated intracellular ROS by demonstrating that a pro-oxidant state amplifies cell proliferation, either via direct stimulation of cell division and activation of transcription or indirectly by inhibiting the execution of the cell death signal. We are working on the premise that sustained elevation of intracellular O2.- in tumor cells could contribute to drug resistance by inhibiting the execution of the death signal. Indeed, in our recent reports, we have shown that pharmacological or endogenous inhibition of intracellular O2.- production enhances tumor cell sensitivity to drug-induced apoptosis. On the contrary, an increase in intracellular O2.- inhibits apoptosis via a direct or indirect effect on caspase activation pathways. We hypothesize that the divergent signaling by ROS is a function of their absolute intracellular concentration and the critical balance between O2.- and H2O2. The critical determinant between survival and apoptotic or necrotic cell death, we believe may be the cytosolic pH, downstream of ROS production. According to our model, survival is favoured with a mild sustainable increase in intracellular O2.- that maintains cytosolic pH in the alkaline range. Apoptosis, on the other hand, is a function of intracellular H2O2 production accompanied by reduction of the intracellular milieu, and more importantly, a decrease in O2.- level and cytosolic acidification. Thus, in order to differentiate necrotic from apoptotic stress, we propose to refer to the mechanism of apoptosis induced by an increase in ROS production as "reductive stress" as opposed to the term "oxidative stress", which should appropriately be used for ROS-induced necrosis.

Principal Investigator: Prof Shazib Pervaiz

Mechanism of cancer prevention and chemotherapeutic potential of wine ingredient resveratrol: In addition to its wide-ranging biological effects, resveratrol prevents tumor formation in murine models of carcinogenesis. We are studying the anti-tumor activity of this compound in vitro and in established neoplasia in mice, as a means to evaluate the chemotherapeutic potential of this naturally occurring compound. In this regard, we demonstrated that the cancer preventive activity of resveratrol could be attributed to its ability to trigger apoptosis in human leukemia and breast carcinoma cells. We also extrapolated these in vitro findings in a murine model of carcinogenesis, and demonstrated in vivo induction of apoptosis in mouse skin papillomas. These findings have significantly enhanced our understanding of the mechanism of action of this chemopreventive agent and more importantly, highlight the great potential of this polyphenolic compound for use as a chemotherapeutic drug.

Principal Investigator: Prof Shazib Pervaiz

Crosstalk between mitochondria and caspase in apoptotic signaling: Recent evidence has highlighted the pivotal role of intracellular cystine proteases (caspases) and mitochondrial-derived apoptogenic factors, such as cytochrome C and AIF, during apoptotic execution. We hypothesize that if the interplay between caspases and mitochondria determine the fate of tumor cells during chemotherapy, then it is logical to identify compounds that directly target these effector components of the death pathway. In this regard, we have shown that the cytosolic release of cytochrome C could occur in the absence of a drop in the transmembrane potential of the mitochondria and without the induction of mitochondrial permeability transition. Secondly, we demonstrated that the mere release of cytochrome C in the absence of efficient caspase activation was not sufficient for effective induction of drug-induced apoptosis. We identified mitochondrial hydrogen peroxide, in addition to cytochrome C release, and downstream induction of cytosolic acidification as critical effector mechanism(s) that determine the efficacy of anti-cancer therapy. These findings have substantially added to our knowledge of the signaling mechanism(s) operative in tumor cells, in particular the role of mitochondria in the execution phase.

Principal Investigator: Prof Shazib Pervaiz

To identify novel anti-cancer agents and develop target specific drugs using the Protein Knock-out Technology: In this respect, the focus is to identify small biologically active agents from natural products or via photoactivation, and develop drugs that permanently knock out the physiological function of target proteins, or enhance the therapeutic indices of antimetabolites using ReceptomicsTM and SM@RTTM Drug Design technologies.

Staff Involved: Prof Shazib Pervaiz, Assoc Prof Lee Chee Wee, Assoc Prof Hooi Shing Chuan

Hepato-oncogenetics: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and retains its ranking as the fourth most frequent cancer in Singapore. It has been shown that genetic changes of hepatocytes occur following exposure to various viral or chemical carcinogens, but the underlying mechanisms of the hepatocarcinogenesis are still largely unknown. The goal of our research is to: 1) identify the genetic changes in human hepatocellular carcinoma; 2) explore the functional significance of these genes; 3) correlate the genetic constitution of individuals' normal and tumor tissue with clinical and epidemiologic information for the evaluation of their joint significance.

The ongoing research projects of our team are:

• Identification of gene differential expression in human hepatocellular carcinoma.

• Characterization of genes which are either down-regulated or up-regulated in hepatocellular carcinoma.

• Exploration of the correlation between hepatic cell behaviour and the differentially expressed genes in cell culture as well as in vivo.

• Evaluation of these genes for correlation to clinicopathological characteristics of hepatocellular carcinoma.

Principal Investigator: Dr Shen Shali

Telomere dysfunction and chromosome instability in tumorigenesis: We are interested in studying the mechanisms by which chromosome stability is influenced by telomere equilibrium. Telomere function may have contrasting roles: inducing replicative senescence (ageing) and promoting tumorigenesis (cancer) depending on the expression of the enzyme telomerase, the level of mutations induced, and efficiency/deficiency of related DNA repair pathways. Work in yeast and mammals has indicated that several factors involved in DNA double-strand break repair are also involved in telomere maintenance. We are using a number of state-of-the-art molecular cytogenetic tools such as quantitative fluorescence in situ hybridization (Q-FISH), multicolour fluorescence in situ hybridization (mFISH), FISH with flow cytometry (Flow-FISH) and multicolour BAND FISH to study the telomerase-mediated chromosome integrity in mammalian cells. Additionally, mouse and human models will be used to study the possible link between telomere dysfunction, chromosome instability, cellular transformation and cancer progression in the evolution of a particular type of tumor. These studies will provide a basis to develop markers for improved diagnosis and therapy of human cancers.

Principal Investigator: A/Prof M. Prakash Hande

Mechanisms and impact of chromosome abnormalities: Complex chromosome abnormalities occur in many malignancies, but underlying mechanisms remain largely unknown. Chromosomal instability can occur when the DNA damage response and repair process fail, resulting in syndromes characterized by growth abnormalities, haematopoietic defects. immunodeficiency, mutagen sensitivity and cancer predisposition. It is important to gain a better understanding of the full genetic and molecular effects of chromosome rearrangements.

Study of chromosome rearrangements is important for many reasons: (1) Chromosome abnormalities account for the majority of cases in infertility and foetal loss in early pregnancy. (2) There exist a significant number of clinical syndromes with specific chromosome abnormalities. (3) Identification and understanding the nature of chromosome rearrangements are very important in the diagnosis, prognosis and therapy of human tumors.

Our laboratory has diverse research interests centering on elucidating the mechanisms and implications of genome instability (functional genomics). We are also interested in studying the effect of chromosome rearrangements on nuclear structures and gene expression. Chromosome analysis of malignant cells provides us with a wealth of information about the genetic and molecular basis of cancer. Chromosome deletions are particularly important as they are frequently accompanied by translocation or other complex chromosome abnormalities. It is important to identify the genes that are lost in chromosome deletions. We will be using state-of-the-art technology such as multicolour fluorescence in situ hybridization (mFISH) to identify chromosome aberrations in human cells. Recently developed mBAND FISH (multicolour banding) will be employed to detect changes within a chromosome such as peri- and para- centric inversions. Chromosome inversions can be very important as they may influence the gene expression pattern on a particular chromosome. mBAND FISH will greatly increase the ease and resolution of inversion analysis. In parallel, techniques such as comparative genomic hybridization (CGH) and cDNA microarray analysis will also be employed.

Research areas:

• Study of distribution and significance of particular chromosomal rearrangements in populations and species and predicting gene map positions by mBAND analysis.

• Relationship between chromosome abnormalities and the process of gene amplification and gene loss.

• Chromosome inversions and cancer.

• Chromatin structure and telomeres.

Principal Investigator: A/Prof M. Prakash Hande

Telomeres and DNA repair factors in ageing and cancer: The ends of chromosomes, or telomeres, consist of short repeated sequences that are synthesized by a ribonucleoprotein-DNA polymerase called telomerase. The RNA component of telomerase is used as a template for the synthesis of new telomeric repeats and is therefore essential for enzyme activity. The maintenance of telomere length by telomerase is essential for chromosomal stability and cell viability and plays an important role in both tumor formation and ageing. The loss of telomere repeats has been causally linked to replicative senescence by the demonstration that overexpression of the enzyme telomerase can result in the elongation or maintenance of telomeres and immortalization of somatic cells with a diploid and apparently normal karyotype. Major questions that remain are related to the actual mechanism by which telomere shortening induces replicative senescence and the importance of telomere shortening and replicative senescence in the homeostasis of cells in renewal tissues and ageing. This perspective is concerned with the consequences of telomere shortening at individual chromosomes in individual cells. Experimental evidence indicates that short telomeres accumulate prior to senescence and that replicative senescence is not triggered by the first telomere to reach a critical minimal threshold length. These observations are compatible with limited repair of short telomeres by telomerase-dependent or telomerase-independent DNA repair pathways. Deficiencies in telomere repair may result in accelerated senescence and ageing as well as genetic instability that facilitates malignant transformation.

Examples of molecules that may have a role in the repair of telomeric DNA prior to replicative senescence include ATM (Ataxia telangiectasia Mutated), p53, PARP [poly(ADP-ribose)-polymerase], DNA-PK and Ku70/80. Currently, we are studying the roles of other related proteins for their role at the telomeres besides repairing the DNA breaks, which in turn are essential for chromosomal/ genomic stability. Our studies using a number of molecular cytogenetic tools may help to determine a possible role of DNA repair genes in telomere biology and hopefully provide as a marker for improved diagnosis and therapy of human tumors.

Principal Investigator: A/Prof M. Prakash Hande

The roles of cytoskeletal proteins in tumour biology: The actin cytoskeleton is a dynamic structure within cells. It responds to a variety of extra- and intracellular signals that direct vital processes such as cell division, differentiation and movement. Our laboratory is interested in how the actin cytoskeleton operates to enhance tumour cell invasion and metastasis. We have shown that modifications of the actin machinery by proteins that bind it (actin depolymerizing factor/ cofilin) can alter tumour cell motility in vitro. This is likely to contribute to the invasive potential of tumour cells. We are investigating if cofilin may influence other cytoskeletal events that contribute to tumour progression.

Principal Investigator: Dr Celestial T. Yap

The role of gelsolin in the oncogenic pathway: Gelsolin is a 82 kDa protein which has several functions in cellular processes, including actin cytoskeletal dynamics, apoptosis and phagocytosis. Besides actin, gelsolin also binds signaling molecules. Several tumours have been found to express reduced levels of gelsolin. These include breast, colon and lung cancers. It is therefore possible that gelsolin normally inhibits tumour-inducing pathways, which are activated with gelsolin downregulation. We aim to test our hypothesis using in vitro and in vivo assays, and correlate the results with observations in clinically-derived tumour samples.

Principal Investigator: Dr Celestial T. Yap

Current Funded Projects:

Role of Heparin/Heparan sulfate interacting protein (HIP) in colon cancer proliferation and differentiation.
Principal Investigator: Assoc Prof Hooi Shing Chuan

Physiological function of nucleoside transporter proteins and uridine phosphorylase in uridine homeostasis and 5-Fluorouracil based anti-tumor therapy.
Principal Investigator: Assoc Prof Lee Chee Wee

Isolation and molecular identification of the equilibrative nucleoside trasporter proteins
Principal Investigator: Assoc Prof Lee Chee Wee

Effector mechanisms that enhance sensitivity of tumor cells to drug-induced apoptosis
Principal Investigator: Prof Shazib Pervaiz

Mechanism of anti-tumor activity of novel anticancer agents generated upon photooxidation of merocyanine 540.
Principal Investigator: Prof Shazib Pervaiz

Investigating the roles of gelsolin in tumourigenesis.
Principal investigator: Dr Celestial T. Yap

Differential gene expression in EL4 lymphoma cells and altered susceptibility to oxysterol-induced cell death: A pilot study to demonstrate a causal relationship.
Principal Investigator: Prof Peter Hwang

BRCA1 and BRCA2 genes in telomere-chromosomal integrity.
Principal Investigator: A/Prof M. Prakash Hande

Use of fluorescence in situ hybridization techniques to study the telomere-chromosome integrity in DNA repair deficient mammalian cells.
Principal Investigator: A/Prof M. Prakash Hande

External Collaborations:

Prof Shazib Pervaiz has active collaborations with the Department of Toxicology, Karolinska Institute, Stockholm, Sweden and the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.

Assoc Prof Lee Chee Wee collaborates with the Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.

Dr Shen Shali has collaborations with the Department of Surgery, Prince of Wales University, Hong Kong and the Department of Physiology, Free University of Brussels, Belgium.

Dr Celestial Yap collaborates with the departments of Surgery at National University Hospital and Singapore General Hospital, and the University of Edinburgh (United Kingdom).

A/Prof M. Prakash Hande has extensive collaborations with the Advanced Medical Discovery Institute, Ontario Cancer Institute, Toronto, Canada, Columbia University, New York, USA, Lawrence Berkeley Laboratory, Berkeley, CA, USA, Radiation Biology Centre, Kyoto University, Kyoto, Japan, Cornell University, USA and the International Agency for Research on Cancer (WHO), Lyon, France.

Selected Publications:

Zhang J, H Wong, S Ramanan, D Cheong, A Leong and SC Hooi (2003) The proline-rich acidic protein is epigenetically regulated and inhibits growth of cancer cell lines. Cancer Res., 63: 6658-6665.

Wang YX, S Tan and SC Hooi (2003) The HIP gene encoding a heparin/heparan sulfate interacting protein is mutated in metastatic human colorectal cancer. Int J Mol Med., 11:473-477.

Tan S, TK Seow, RCMY Liang, S Koh, CPC Lee, MCM Chung and SC Hooi (2002) Proteome analysis of butyrate-treated human colon cancer cells (HT-29). Int J Cancer, 98: 523-531.

Ni HM, AF Leong, D Cheong and SC Hooi (2002) Expression of CD44 variants in colorectal carcinoma quantified by real-time reverse transcriptase-polymerase chain reaction. J Lab Clin Med., 139: 59-65.

Wang Y, C Hung, D Koh, D Cheong and SC Hooi (2001) Differential expression of Hox A5 in human colon cancer cell differentiation: a quantitative study using real-time RT-PCR. Int J Oncol., 18: 617-622.

Zhang J, N Rajkumar and SC Hooi (2000) Characterization and expression of the mouse pregnant specific uterus protein and its rat homologue in the intestine and uterus. Biochim Biophys Acta, 1492: 526-530. 

Wang Y, D Cheong, S Chan and SC Hooi (2000) Ribosomal protein L7a gene is up-regulated but not fused to the tyrosine kinase receptor as chimeric trk oncogene in human colorectal carcinoma. Int J Oncol., 16: 757-762.

Tan S and SC Hooi (2000) Syncollin is differentially expressed in rat proximal small intestine and regulated by feeding behaviour. Am J Physiol Gastrointest Liver Physiol., 278: G308-G320. 

Ren J, JI Koenig and SC Hooi (1999) Stimulation of anterior pituitary galanin and prolactin gene expression in suckling rats. Endocrine, 11:251-256.

Wang Y, D Cheong, S Chan and SC Hooi (1999) Heparain/heparan sulfate interacting protein gene expression is up-regulated in human colorectal carcinoma and correlated with differentiation status and metastasis. Cancer Research, 59: 2989-2994. 

Wang Y, S Tan and SC Hooi (1999) Identification and characterization of a novel rat triosephosphate isomerase gene in remnant ileum after massive small bowel resection. Dig Dis Sci., 44: 25-32.

Pervaiz S (2003) Resveratrol: from grapevines to mammalian biology. FASEB J., 17: 1975-1985.

Clement MV, JL Hirpara and S Pervaiz (2003) Decrease in intracellular superoxide sensitizes Bcl-2-overexpressing tumor cells to receptor and drug-induced apoptosis independent of the mitochondria. Cell Death Differ., 10(11): 1273-1285.

Pervaiz S (2002) Anti-cancer drugs of today and tomorrow: are we close to making the turn from treating to curing cancer? Curr Pharm Des., 8: 1723-1734.

Pervaiz S and MV Clement (2002) Hydrogen peroxide-induced apoptosis: oxidative or reductive stress? Methods Enzymol., 352: 150-159.

Pervaiz S and MV Clement (2002) A permissive apoptotic environment: function of a decrease in intracellular superoxide anion and cytosolic acidification. Biochem Biophys Res Comm., 290: 1145-1150.

Clement MV and S Pervaiz (2001) Intracellular superoxide and hydrogen peroxide concentrations: a critical balance that determines survival or death. Redox Rep., 6: 211-214.

Pervaiz S, J Cao, OS Chao, YY Chin and MV Clement (2001) Activation of the Rac GTPase inhibits apoptosis in human tumor cells. Oncogene,  20: 6263-6268.

Pervaiz S (2001) Resveratrol- from the bottle to the bedside? Leuk Lymphoma, 40: 491-498.

Pervaiz S (2001) Reactive oxygen-dependent production of novel photochemotherapeutic agents. FASEB J., 15: 612-617.

Hirpara JL, MV Clement and S Pervaiz (2001) Intracellular acidification triggered by mitochondrial-derived hydrogen peroxide is an effector mechanism for drug-induced apoptosis in tumor cells. J. Biol. Chem., 276(1): 514-521.

Hirpara JL, MA Seyed, H Dong, M Kini and S Pervaiz (2000) Induction of mitochondrial permeability transition and cytochrome C release in the absence of caspase activation is insufficient for effective apoptosis in human leukemia cells. Blood, 95(5): 1773-1780.

Moh MC, LH Lee, X Yang and S Shen (2003) HEPN1, a novel gene that is frequently down-regulated in hepatocellular carcinoma, suppresses cell growth and induces apoptosis in HepG2 cells. J Hepatol., 39: 580-586.

Bourgain RH, M Paubert-Braquet, S Shen, K Decuyper, E Biochot-Lagente and R Andries (1994) An optoelectronic registration method as applied to PAF-mediated hydrogen peroxide induced arterial thrombosis. J Lipid Mediat Cell Signal, 9(1): 79-88.

Shen S, R Andries, R De Zanger, F Vereecke and RH Bourgain (1994) induction and registration of changes in arteriolar vasomotor tone in vivo: description of a method. Jap J Thromb Hemo, 5: 262-274.

C.T. Yap, T.I. Simpson, T. Pratt, D.J. Price, S.K. Maciver (2005). The motility of glioblastoma tumour cells is modulated by intracellular cofilin expression in a concentration-dependent manner. Feature paper in Cell Motility and the Cytoskeleton 2005 Jan20; 60(3):153-165.

Abraham J, B Lemmers, MP Hande, ME Moynahan, C Chahwan, A Ciccia, J Essers, K Hanada, R Chahwan, AK Khaw, P McPherson, A Shehabeldin, R Laister, C Arrowsmith, R Kanaar, SC West, M Jasin and R Hakem (2003) Eme1 is involved in DNA damage processing and maintenance of genomic stability in mammalian cells. EMBO J., 22: 6137-6147.

Hande MP, TV Azizova, CR Geard, LE Burak, CR Mitchell, VF Khokhryakov, FK Vasilenko and DJ Brenner (2003) Past exposure to densely ionizing radiation leaves a unique permanent signature in the genome. Am J Hum Genet.,72: 1162-1170.

Cheung AMY, MP Hande, F Jalali, MS Tsao, B Skinnider, A Hirao, JP McPherson, J Karaskova, A Suzuki, A Wakeham, A You-Ten, A Elia, JA Squire, R Bristow, R Hakem and TW Mak (2002) Loss of Brca2 and p53 synergistically promotes genomic instability and deregulation of T-cell apoptosis. Cancer Res.,62: 6194-6204.

Tong W-M, U Cortes, MP Hande, H Ohgaki, LR Cavalli, PM Lansdorp, BR Haddad and Z-Q Wang (2002) Synergistic role of Ku80 and poly (ADP-ribose) polymerase in suppressing chromosomal aberrations and liver cancer formation. Cancer Res., 62(23): 6990-6996.

Wood LD, TL Halvorsen, S Dhar, JA Baur, RK Pandita, WE Wright, MP Hande, G Calaf, TK Hei, F Levine, JW Shay, JJY Wang and TK Pandita (2001) Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression. Oncogene, 20:278-288.

Hande MP, AS Balajee, A Tchirkov, A Wynshaw-Boris and PM Lansdorp (2001) Extra-chromosomal telomeric DNA in cells from Atm-/- mice and patients with ataxia-telangiectasia. Hum Mol Genet., 10: 519-528.

Tong W-M, MP Hande, PM Lansdorp and Z-Q Wang (2001) DNA strand break-sensing molecule PARP cooperates with p53 in telomere function, chromosome stability and tumor suppression. Mol Cell Biol., 21: 4046-4054.

d'Adda di Fagagna F, MP Hande, WM Tong, D Roth, PM Lansdorp, ZQ Wang and SP Jackson (2001) Effects of DNA non-homologous end-joining factors on telomere length and chromosome stability in mammalian cells. Curr Biol., 11: 1192-1196.

Gilley D, H Tanaka, MP Hande, A Kurimasa, GC Li, M Oshimura and DJ Chen (2001) DNA-PKcs is critical for telomere capping. Proc Nat Acad Sci USA, 98: 15084-15088.

Niida H, Y Shinkai, MP Hande, T Matsumoto, S Takahara, M Tachibana, M Oshimura, PM Lansdorp and Y Furuichi (2000) Telomere maintenance in telomerase deficient mouse embryonic stem cells: Characterization of an amplified telomeric DNA. Mol Cell Biol., 20: 4115-4127.

Liu Y, BE Snow, MP Hande, G Baerlocher, V Kickhoefer, D Yeung, D Wakeham, A Itie, DP Siderovski, PM Lansdorp, MO Robinson and L Harrington (2000) The telomerase-associated protein TEP1 is not essential for telomerase activity or telomere length maintenance in vivo. Mol Cell Biol., 20: 8178-8184.

Liu Y, BE Snow, MP Hande, D Yeung, NJ Erdmann, A Wakeham, A Itie, DP Siderovski, PM Lansdorp, MO Robinson and L Harrington (2000) The telomerase reverse transcriptase is limiting and necessary for telomerase function in vivo. Curr Biol., 10: 1459-1462.

Hsu H-L, D Gilley, SA Galande, MP Hande, B Allen, S-H Kim, GC Li, J Campisi, T Kohwi-Shigematsu and DJ Chen (2000) Ku acts in unique way at the mammalian telomere to prevent end joining. Genes Dev., 14: 2807-2812.

Hande MP, E Samper, P Lansdorp and MA Blasco (1999) Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J Cell Biol.,144: 589-601.

Hande P, P Slijepcevic, A Silver, S Bouffler, P van Buul, P Byrant and P Lansdorp (1999) Elongated telomeres in SCID mice. Genomics, 56: 221-223.

d'Adda di Fagagna F, MP Hande, WM Tong, PM Lansdorp, ZQ Wang and SP Jackson (1999) Functions of poly(ADP-ribose) polymerase in controlling telomere length and chromosomal stability. Nat Genet, 23: 76-80.

Surralles J, MP Hande, R Marcos and PM Lansdorp (1999) Accelerated telomere shortening in the human inactive X-chromosome. Am J Hum Genet, 65: 1617-1622.

Current Activities:

Working-in-Progress Seminars (WIPS): bi-weekly work-in-progress seminars are conducted in the Department of Physiology on Fridays, where graduate students and Principal Investigators from all four research programmes take turns to present their ongoing research activities.

Job Opportunities:

The Apoptosis and Cancer Biology programme is inviting applications for appointment at the Assistant/ Associate Professor, post-doctoral and graduate student levels. Interested applicants should forward a copy of their curriculum vitae with the names of three referees to:

Prof Shazib Pervaiz,
MBBS, PhD
Department of Physiology
Yong Loo Lin School of Medicine
National University of Singapore
MD9, 2 Medical Drive
Singapore 117597
  Tel: +65 6874 6602
Fax: +65 6778 8161
Email: phssp@nus.edu.sg