Calendar Name: seminars
Scheduled for: Tuesday, May 8 2012, 14:00 - 15:30
Event text: Prof Salvador Moncada
Wolfson Institute for Biomedical Research
University College London
London
UNITED KINGDOM
Details: �Connecting cell cycle progression to metabolic
requirements�
ABSTRACT
Cell proliferation is accompanied by an increase in the
utilization of glucose and glutamine. The proliferative
response is dependent on a decrease in the activity of
the ubiquitin ligase anaphase-promoting
complex/cyclosome (APC/C)-Cdh1 which controls G1-
to-S-phase transition by targeting degradation motifs,
including the KEN box. This occurs not only in cell
cycle proteins but also in the glycolysis-promoting
enzyme
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
isoform 3 (PFKFB3), as we have demonstrated in cells in
culture as well as in proliferating human T lymphocytes.
Moreover, we have found that glutaminase 1 is a
substrate for this ubiquitin ligase and appears at the
same time as PFKFB3 in proliferating cells. Glutaminase
1 is the first enzyme in glutaminolysis and converts
glutamine to glutamate, yielding intermediates for cell
proliferation. Thus APC/C-Cdh1 is responsible for the
increased utilization not only of glucose but also of
glutamine and, as such, accounts for the critical step
that links the cell cycle with the metabolic substrates
essential for its progression. A further degree of
control is provided by a second ubiquitin ligase � SCF
(Skp1/CUL-1/F-box protein)--TrCP � which causes
the disappearance of PFKFB3 during late G1/S. Thus the
presence of PFKFB3 is tightly controlled to ensure the
upregulation of glycolysis at a specific point in G1.
The relevance of these observations to understanding of
the proliferative and metabolic changes that occur in
normal and in cancer cells will be discussed.
