Molecular Signalling Laboratory

Laboratory Head
Associate Professor Jun-Ping Liu

Research Fellow
Dr. He Li

Visiting Scientists
Dr. Ying Ju
Dr. Jing Jia
Dr. Ying Tang

PhD Students
Lucy Cassar
Jian Chan
Julie Dwyer
Craig Nicolls
Alex Pinto

Honours Student
Cheong Cheng
Charley Mackenzie-Kludas
Bao Wong

Investigation of molecular basis of cell ageing: changes in molecular switches of cell lifespan and transport

Switch for cell lifespan
Human cells possess finite lifespan with various developing programs that are followed by cell ageing. Ageing is determined by both genetic and metabolic factors. To a large part, the detailed mechanisms of cell ageing remain to be unexplored. Genetically, the timing of cell ageing entails the loss of telomeres (tips of chromosomes).

Telomeres comprise extended arrays of a few thousand tandem repeat sequences of TTAGGG complementary strands, and their binding proteins. Protecting chromosome ends from recombination, fusion and degradation, telomeres also undergo progressive shortening as cells divide due to the inability of conventional DNA polymerase to replicate the extreme ends of chromosomes and to the activity of a putative 5’-3’ exonuclease. When the telomeres are critically short, cells exit the cell division cycle, characteristic of cell ageing.

As a measure to maintain telomeres for continuous renewal and proliferation of stem cells, the enzyme telomerase has evolved to synthesize telomeres by reverse transcription. Telomerase is a large ribonucleoprotein complex containing the catalytic subunit telomerase reverse transcriptase (TERT) and the RNA template. To date, if telomerase has other functions in cells and how telomerase program of telomere lengths is regulated by extracellular cytokines to achieve immortality such as in cancer are hot topics among vigorous investigations.

Maintaining healthy brain
To prevent premature ageing and loss of neurons in brain, a fundamental issue is to maintain an ordered and continuous movements of transport molecules in and between neurons. Metabolic accumulation of peptides, lipids and reactive oxygen species, in any locations of the neurons, causes nerve cell ageing and death. Having cloned a novel ATPase transporter predominantly expressed in neurons, we are investigating the structural and functional relationship in molecular transport.

Current Research Projects:
1. Cytokine regulation of telomerase activity in cancer.
2. Mechanisms of telomerase inhibition by small molecules in cancer
3. Structure-function of a novel ATPase in molecular trafficking

Publications:
Sharyn Bayne, Margaret Jones, He Li, Evan Simpson, Jun-Ping Liu (2007) Estrogen deficiency results in decreases of telomerase activity and cell proliferation in the adrenal gland of mice. Submitted.

Sharyn Bayne, Margaret E.E. Jones, He Li and Jun-Ping Liu (2007) Potential roles for estrogen regulation of telomerase activity in aging. Annals of The New York Academy of Sciences , in press

He Li and Jun-Ping Liu (2007) Mechanisms of action of TGFb in cancer: evidence for Smad3 as a repressor of the hTERT gene. Annals of The New York Academy of Sciences , in press

Julie Dwyer, He Li, Dakang Xu and Jun-Ping Liu (2007) Transcriptional regulation of telomerase activity: roles of the Ets transcription factor family. Annals of The New York Academy of Sciences , in press

He Li, Indzi Katik, Jun-Ping Liu (2007) Uses of telomerase peptides in anti-tumor immune therapy. "Telomerase Inhibition: Strategies and Protocols", Methods in Molecular Biology, Edited by L. G. Andrews and T. O. Tollefsbol, Vol. 000: 61-86, in press

Dakang Xu, He Li, Jun-Ping Liu (2007) Inhibition of telomerase by targeting MAP kinase signaling. "Telomerase Inhibition: Strategies and Protocols", Methods in Molecular Biology, Edited by L. G. Andrews and T. O. Tollefsbol, Vol. 000: 147-165, in press

Shanhong Ling, Liemin Zhou, He Li, Aozhi Dai, Jun-Ping Liu, Paul A. Komesaroff, Krishnankutty Sudhir (2006) Effects of 17b-estradiol on proliferation and survival of human vascular endothelial cells in repsonse to mechanical strain and tumor necrosis factor-a . Steroids, 71: 799-808.

He Li, Dakang Xu, Jinhua Li, Michael Berndt, Jun-Ping Liu (2006) Transforming growth factor beta suppresses human telomerase reverse transcriptase by Smad3 interactions with c-Myc and hTERT gene. J Biol Chem, 281(35): 25588-600 .

Jun-Ping Liu, Lucy Cassar, Alex Pinto, He Li (2006) Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal cancer. Cell Research, 16: 809-817.

He Li, Dakang Xu, Ban-Hock Toh, Jun-Ping Liu (2006) TGF-b and Cancer: Is Smad3 a repressor of hTERT gene? Cell Research, 16: 169-173

Jun-Ping Liu, Alex Pinto, He Li (2005) Telomerase down-regulation and PC12 pheochromocytoma cell differentiation: Roles of MAP kinase signaling. Proceedings of International Academy of Pathology, published by MEDIMOND SRL International Proceedings, Beijing. F823: 269-277.

Sharyn Bayne, Jun-Ping Liu (2005) Hormones and growth factors regulate telomerase activity in ageing and cancer. Mol Cell Endocrinol., 240:11-22.

He Li, Alex Pinto, Wenzhou Duan, Jinhua Li, Ban Hock Toh, Jun-Ping Liu (2005) Telomerase down-regulation does not mediate PC12 pheochromocytoma cell differentiation induced by NGF, but requires MAP kinase signaling. J Neurochemistry, 95: 891-901.

Bayne S and Liu JP. Hormones and growth factors regulate telomerase activity in ageing and cancer. Mol Cell Endocrinol. 2005; 240: 11-22.

Li H and Liu JP. Signaling on telomerase: a master switch in cell aging and immortalization. Biogerontology. 2002; 3: 109-118.

Cao Y, Li H, Mu F-T, Ebisui O, Funder JW and Liu JP. Telomerase activation causes vascular smooth muscle cell proliferation in genetic hypertension. FASEB J. 2002; 16: 96-98.

Cao Y, Li H, Deb S and Liu JP. TERT regulates cell survival independent telomerase activity. Oncogene. 2002; 21: 3130-3138.

Liu JP. Molecular mechanisms regulating telomerase activity. In Telomerase, aging and disease. M. P. Mattson MP and Pandita T (Eds.) Elsevier Science, The Netherlands. 2001. pp33-59.

Liu JP. Telomerase: Not just black and white, but shades of gray. Mol Cell Biol Res Commun. 2000; 3: 129-135.

Liu JP. Studies of the molecular mechanisms in the regulation of telomerase activity. FASEB J. 1999; 13: 2091-2104.

Li H, Cao Y, Berndt MC, Funder JW and Liu JP. Molecular interactions between telomerase and the tumor suppressor protein p53 in vitro. Oncogene. 1999; 18: 6785-6794.

Li H, Zhao L, Yang Z, Funder JW and Liu JP. Telomerase is controlled by protein kinase Calpha in human breast cancer cells. J Biol Chem. 1998; 273: 33436-33442.

Li H, Zhao LL, Funder JW and Liu JP. Protein phosphatase 2A inhibits nuclear telomerase activity in human breast cancer cells. J Biol Chem. 1997; 272: 16729-16732.

Switch for cell transport
Transport of molecules constitutes a significant part of total cell activity. Excess trafficking of lipids from the Golgi apparatus causes early cell ageing and death. Little is known about how various molecules such as lipids transport between different locations within cell is controlled.

Communication between cells occurs with discontinuous flows of molecules from one location to another. It involves not only extracellular transport mediated by plasma membrane channels, pumps, transporters and exocytic and endocytic vesicles, but also intracellular trafficking sub served by a number of organelles including the endoplasmic reticulum (ER), the Golgi apparatus and the endosome-lysosome systems. Sequentially ordered cellular trafficking and signalling events are required for normal cell function.

Although much information has accrued on the molecular mechanisms underlying inter and intracellular trafficking over the past decade, we have an incomplete picture of the relevant regulatory proteins and effectors that operate at the ER-Golgi and endosome-lysosome systems particularly in disease. Studies from our laboratory have been focused on key enzymes such as GTPase and ATPase that may switch on and off certain cell transport steps.

Recently, we have cloned a novel enzyme that may function as a specialist lipid transporter. We will determine how this enzyme controls lipid traffic during cell development and maturity. This study will unveil important mechanisms of molecular transport under various conditions.

Current Research Projects:
1. Investigation of protein interaction of a novel ATPase in membrane trafficking
2. Quality and quantity analysis of the novel ATPase in cell ageing and stress
3. Developmental studies of the novel ATPase gene regulation

Publications:
Yang Z, Li H, Chai Z, Fullerton MJ, Cao Y, Toh BH, Funder JW and Liu, J. P. Dynamin II regulates hormone secretion in neuroendocrine cells. J Biol Chem. 2001; 276: 4251-4260.

Liu JP, Yajima Y, Li H, Ackland S, Akita Y, Stewart J and Kawashima S. Molecular interactions between dynamin and G-protein betagamma-subunits in neuroendocrine cells. Mol Cell Endocrinol. 1997; 132: 61-71.

Liu JP. The discovery of GTP-binding protein dynamin and mechanisms of synaptic vesicle recycling in neurotransmission. Prog Physiol Sci. 1997; 28: 55-57.

Liu JP.Protein phosphorylation events in exocytosis and endocytosis. Clin Expt Pharmacol Physiol. 1997; 24: 611-618.

Liu JP. Dynamic dynamin. Today's Life Science. 1996; 8: 23-26.

Liu JP, Zhang QX, Baldwin G and Robinson PJ. Calcium binds dynamin I and inhibits its GTPase activity. J Neurochem. 1996; 66: 2074-2081.

Liu JP. Protein kinase C and its substrates. Mol Cell Endocrinol. 1996; 116: 1-29.

Liu JP and Robinson PJ. Dynamin and endocytosis. Endocrine Reviews. 1995; 16: 590-607.

Robinson PJ, Liu JP, Powell KA, Fykse EM and Sudhof TC. Phosphorylation of dynamin I and synaptic vesicle recycling. Trends in Neurosci. 1994; 17, 348-353.

Liu JP, Sim ATR and Robinson, PJ. Calcineurin inhibition of dynamin I GTPase activity is coupled to nerve terminal depolarization. Science. 1994; 265: 970-973.

Liu JP, Powell KA, Sudhof  TC and Robinson PJ. Dynamin is a calcium-sensitive phospholipid-binding protein with very high affinity for protein kinase C. J Biol Chem. 1994; 269: 21043-21050.

Liu JP, Engler D, Funder JW and Robinson PJ. Arginine vasopressin (AVP) causes the reversible phosphorylation of the myristoylated alanine-rich C kinase substrate (MARCKS) protein in the ovine anterior pituitary. Evidence that MARCKS phosphorylation is associated with adrenocorticotropin (ACTH) secretion. Mol Cell Endocrinol. 1994; 101: 247-256.

Sontag JM, Fykse EM, Ushkaryov Y, Liu JP, Robinson PJ and Sudhof TC. Differential expression and regulation of multiple dynamins. J Biol Chem. 1994; 269: 4547-4554.

Robinson PJ, Sontag JM, Liu JP, Fykse EM, Slaughter C, McMahon H and Sudhof TC. Dynamin GTPase regulated by protein kinase C phosphorylation in nerve terminals. Nature. 1993; 365: 163-166.

Liu JP, Clarke I J, Funder JW and Engler D. Studies of the secretion of corticotropin-releasing factor and arginine vasopressin into the hyperphysical-portal circulation of the conscious sheep. J Clin Invest. 1994; 93: 1439-50

Liu JP, Engler D, Funder JW and Robinson PJ. Evidence that the stimulation by arginine vasopressin (AVP) of the release of adrenocorticotropin (ACTH) from the ovine anterior pituitary involves the activation of protein kinase C. Mol Cell Endocrinol. 1992; 87: 35-47.

Liu JP, Clarke I J, Funder JW and Engler D. Evidence that the central noradrenergic and adrenergic pathways activate the hypothalamic-pituitary-adrenal (HPA) axis in the sheep. Endocrinology. 1991; 129: 200-209.

Liu JP, Robinson PJ, Funder JW and Engler D. The biosynthesis and secretion of adrenocorticotropin by the ovine anterior pituitary is predominantly regulated by arginine vasopressin (AVP).  Evidence that protein kinase C mediates the action of AVP. J Biol Chem. 1990; 265: 14136-14142.

For more information on any of the work being carried out in this laboratory please contact Associate Professor Jun-Ping Liu
Email: jun-ping.liu@med.monash.edu.au
Phone: (03) 9903 0715