REGULATION OF LIVER GROWTH AND FUNCTION

Project: Research project

Project Details

Description

Disorders of protein metabolism in the liver are a principal feature of
the pathogenesis of diabetes and other disease states that affect nutrient
homeostasis. Development of strategies for the treatment of these
disorders requires knowledge of the basic events involved in the
regulation of hepatic protein metabolism. Therefore, the overall goal of
this project is to provide a better understanding of the mechanisms by
which hormones and nutrients regulate specific events in the path way of
protein synthesis in the liver. The focus of the project continues to be
on peptide-chain initiation, a process which is mediated by a series of
proteins termed eukaryotic initiation-factors (abbreviated eIF) and which
is a major control point for the regulation of mRNA translation in
eukaryotic cells. Our previous work has established important roles for
three initiation factors in the regulation of hepatic protein synthesis
under conditions such as diabetes, deprivation of single essential amino
acids, and depletion of calcium from the endoplasmic reticulum. The latter
two conditions lead to increased phosphorylation of the alpha-subunit of
eIF-2, a heterotrimeric protein which mediates the binding of initiator
tRNA (Met-tRNAi) to the ribosome as a ternary complex (eIF-2.GTP.Met-
tRNAi), and to decreased activity of eIF-2B, a heteropentameric protein
which mediates guanine nucleotide exchange on eIF-2. The former condition
leads to reduced function of eIF-4F, a heterotrimeric protein which
mediates binding of mRNA to the 43S preinitiation complex. Presently,
little is known about the regulation of these initiation factors.
Therefore, the studies proposed in this application are designed to
further elucidate the function and regulation of eIF-2, eIF-2B, and eIF-
4F, particularly their role in the control of hepatic protein synthesis
under conditions of altered hormonal or nutrient status. The specific aims
of the studies are: (l) to clone, sequence, and express cDNAs encoding all
five subunits of eIF-2B, investigate mechanisms involved in the regulation
of eIF-2B activity including the roles of phosphorylation and allosteric
factors, and examine the role of each subunit in terms of eIF-2B activity
and regulation; (2) to clone,, sequence, and express cDNAs encoding elF-
2alpha: kinases, investigate the mode of regulation of each kinase, and
examine the role of each kinase in mediating increased phosphorylation of
eIF-2alpha under the physiological conditions described in the next two
aims; (3) to investigate the involvement of a protein kinase cascade in
the signal transduction path way by which depletion of calcium from the
lumen of the endoplasmic reticulum results in increased phosphorylation of
eIF-2alpha; (4) to identify and characterize the eIF-2alpha phosphatase
and to investigate the possible role of an eIF-2alpha kinase in the
mechanism by which deprivation of single essential amino acids results in
increased phosphorylation of elF-2alpha; and (5) to test the hypothesis
that insulin regulates peptide-chain initiation in liver by modulating the
expression and/or state of phosphorylation of one or more of the subunits
of eIF-4F. Overall, the studies described in this proposal should help
identify mechanisms by which hormones and nutrients regulate protein
synthesis in the liver. They should also provide new insights into the
biochemical and molecular mechanisms involved in the initiation of protein
synthesis.
StatusFinished
Effective start/end date2/1/951/31/96

Funding

  • NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

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