Consequences of Stress in the Secretary Pathway: The ER Stress Response and Its Role in the Metabolic Syndrome - Protein Misfolding and Cellular Stress in Disease and Aging - page 52

ATF4 by PERK ( 121, 124 ) and induction of ORP150, which is
required for VEGF-A secretion. Furthermore, IRE1a is also
required for induction of VEGF-A in tumors ( 125 ). Tumor
growth and vascularization was decreased in transgenic mice
expressing a dominant-negative form of IRE1a compared to WT
mice ( 125 ). These findings have let to the proposal to exploit
inhibition of the UPR and of ER chaperones as a new chemo-
therapeutic strategy.
What activates the UPR in hypoxia and ischemia? Glucose
depletion and ROS are two candidates. Glucose depletion induces
ER chaperones ( 126, 127 ) through depletion of cellular ATP
stores, stalling of chaperone ATPase cycles and inhibition of
N -linked glycosylation. Ischemia generates superoxide and NO
radicals, which, as discussed above, oxidatively damage proteins
and may irreversibly deplete ER Ca 2+ -stores by activating ryano-
dine receptors and inhibiting SERCA Ca 2+ pumps ( 128 ).
4. Conclusions
Research into the UPR has revealed a surprisingly direct link
between protein metabolism in the ER and energy metabolism
pointing toward a central role for ER stress in energy homeostasis
in mammals. UPR signaling is also linked to nitrogen metabolism
in the unicellular eukaryote Saccharomyces cerevisiae ( 109, 110 ),
indicating that control of metabolism by the UPR has evolved in
lower eukaryotes. Future studies using mouse models will con-
tinue to unravel the contribution of the UPR to energy homeo-
stasis in mammals. Considering the apparent conservation of the
role of the UPR in metabolism, additional studies in other eukary-
otic model organisms should be encouraged, which, for example,
in yeast may contribute to unraveling functions of the IRE1
branch of the UPR in the absence of insulin, but not necessarily
glucose, signaling. Despite the exciting finding of the importance
of ER stress in the metabolic syndrome, open questions remain-
ing in the UPR proper will need to be addressed in future work.
Important future research directions include the identification of
the 'ER stress' sensing mechanism employed by IRE1, PERK,
and ATF6, the identification of how UPR signaling controls cell
fate, that is, to answer the question why UPR signaling promotes
cell survival in one situation and apoptosis in another, and last,
but not least, the identification of negative regulatory mecha-
nisms turning off the UPR once ER stress has been resolved.
Addressing the first and last questions will benefit from studies in
eukaryotic model organisms such as yeast, as evolutionary graft-
ing of additional layers of regulation onto basic regulatory mech-
anisms is likely to complicate studies in mouse or human cells.