CIHR-UBC Strategic Training Program for
Translational Research in Infectious Diseases
Address: D452 – 2733 Heather Pavilion, Vancouver, BC V5Z 3J5
E-mail: tonychow@interchange.ubc.ca
Voice: (604) 875-5063 Fax: (604) 875-4013 Website: http://cmdr.ubc.ca/trainingprogram
Research Theme:
Molecular pathogenesis, innate immunity, cell signalling, immunomodulation
Sub-theme:
Signalling events controlling cytokine-dependent survival of inflammatory cells
Principal Investigator:
Dr. Vincent Duronio, PhD
Telephone:
Fax:
E-mail:
604-875-4707
604-875-4497
vduronio@interchange.ubc.ca
The death of inflammatory cells by apoptosis, and their subsequent clearance, represents an essential step in the
regulation of many processes. Besides blood homeostasis, apoptosis of cells is critical in clearing cells from sites of
inflammation, and thus it may also play a role in the regulation of inflammatory cells involved in transplant rejection.
Work in our laboratory is contributing to a better understanding of the molecular mechanisms by which inflammatory
cells undergo apoptosis. Cytokine-dependent hemopoietic cell lines, as well as primary cells that are kept alive by
cytokines, are used to investigate the key pro-survival signals mediated by cytokines. Our group was among the first to
show that a very important element of cell survival is via the PI 3-kinase signalling pathway. We have continued to
characterize the components of this signalling pathway and have recently concentrated on phosphorylation of the
forkhead family of transcription factors by PKB/akt. Cytokine-dependent phosphorylation of FKHRL1 is inhibitory and
loss of phosphorylation was shown to increase forkhead transcriptional activity, and stimulate production of FasL. The
resulting up-regulation of FasL was also shown to coincide with increased Fas receptor expression, and activation of the
intrinsic apoptosis cascade. Thus, we have made the exciting discovery that Fas-mediated death may play a more
important role than mitochondrial-mediated events in apoptosis of some types of inflammatory cells.
Future work in this project will continue to characterize the caspase cascades that operate in various primary
inflammatory cells, concentrating on the ordering of the activation of caspases 8 and 9 (i.e. relative importance of Fas
vs. mitochondrial death). We know that pro-survival Bcl-2 family members can block apoptosis following cytokine
withdrawal, and we will investigate how they affect the Fas-dependent events. Modulation of the Fas-dependent death
will be attempted using external means of blocking the Fas receptor, or FasL, as well as by expressing dominant
negative forms of intermediate signalling components such as FADD. This research is crucial to help us understand how
various hemopoietic cells may be stimulated to undergo apoptosis.
Scheid MP, Schubert KM, Duronio V. Regulation of bad phosphorylation and association with BcIXL by the
MAPK/ERK kinase. J Biol Chem 274:31108-31113 (1999).
Schubert KM, Scheid MP and Duronio V. Ceramide inhibits PKB activity by promoting dephosphorylation of Ser473. J
Biol Chem 275:13330-13335 (2000).
Schubert KM and Duronio V. Distinct roles for extracellular signal regulated protein kinase (ERK) mitogen-activated
protein kinases and phosphatidylinositol 3-kinase in the regulation of Mcl-1 synthesis. Biochem J. 356:473-480 (2001)
Dramsi S, Scheid MP, Maiti A, Hojabrpour P, Chen X, Schubert K, Goodlett DR, Aebersold R and Duronio V.
Identification of a novel phosphorylation site, Ser170, as a regulator of bad pro-apoptotic activity. J Biol Chem.
277:6399-6405 (2002)
Denny T and Duronio V. Hemopoietic cells undergo Fas-mediated apoptosis following cytokine withdrawal: Role of
PKB-dependent regulation of FKHRL1 phosphorylation and FasL expression. Submitted to J. Immunol., in revision.
Updated: August 2003
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