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Wu and colleagues
used 2 cell models to study the effects of insulin-like growth
factor-I receptor (IGF-IR) signaling via insulin receptor substrate
(IRS)-1 on the upstream binding factor 1 (UBF1), a regulator of
ribosomal RNA (rRNA) synthesis. 32D cells (myeloid cells dependent on
interleukin-3 (IL-3) for growth) express neither IRS-1 nor IRS-2. In
complement, mouse embryo fibroblasts (MEFs) express IRS-1 but have a
targeted disruption of the IGF-IR gene (R– cells).
Apoptosis normally
takes place in 32D cells upon removal of IL-3. 32D cells expressing
IGF-IR (32D IGF-IR cells) continue growing for 48 hours after IL-3 is
replaced with IGF-I, and then undergo granulocyte differentiation.
32D IGF-IR cells ectopically expressing IRS-1 grow indefinitely
without differentiation. R– cells were also used to
develop sister cells for comparison. R–/T cells
express the SV40 large T antigen, while R+ cells have the
IGF-IR reintroduced. IRS-1 is mostly nuclear in IGF-I-stimulated R+
cells and in R–/T cells, but cytoplasmic in the
parental R– cells.
Using these 2
systems, the authors showed that IGF-I increased transcription from
the rDNA promoter (ie, activated UBF1) in a time course compatible
with nuclear translocation of IRS-1. Since UBF1 activation generally
occurs via phosphorylation, additional experiments showed that UBF1
phosphorylation, mainly in the C terminus, was IGF-I stimulated and
IRS-1 dependent. Beyond that, UBF1 regulation in the 2 cell models
differed. In the myeloid cells deprived of IL-3, 32D IGF-IR/IRS-1
cells died without IGF-I, but maintained high levels of UBF1 protein
when stimulated with IGF-I. The 32D IGF-IR cells (ie, without IRS-1)
had high UBF1 protein levels, which dropped at 48 hours (ie, while
the cells were still growing exponentially and not yet showing any
morphologic signs of differentiation) and completely disappeared by
the time the cells were differentiated into granulocytes. The drop in
UBF1 protein was due to both decreased synthesis and increased
degradation, though UBF1 mRNA levels remained unchanged. In the MEFs,
cells that do not differentiate, UBF1 protein levels were stable
after IGF-I treatment in both R+ and R–
cells. Thus, the authors concluded that IGF-IR/IRS-1 signaling
regulates UBF1 activity, and hence the rDNA promoter, through
phosphorylation and in some cells, through changes in protein level.
UBF1 protein loss may be related to the differentiation process,
which tends to involve nucleolar dissolution.
Wu
A, Tu X, Prisco M, Basergo R. Regulation of upstream binding factor I
activity by IGF-I receptor signaling. J Biol Chem 2005; 280:2863-72.
Editor’s
Comment: IGF signaling through the IGF-IR is understood to
stimulate cellular survival and proliferation, and at the systemic
level, growth. IGF-IR is a tyrosine kinase that is activated by
ligand binding. Phosphorylation of tyrosine residues in IGF-IR
recruits adaptor molecules like IRS-1 that then start kinase
cascades, most notably the PI3 kinase/Akt pathways and the MAP kinase
pathway (for reviews, see References 1-2). The paper by Wu et al adds
another mechanism whereby IGF-IR signaling stimulates growth:
activation of UBF1 through nuclear translocated IRS-1 and presumably
PI3 kinase. UBF1 regulates RNA polymerase I activity at the rDNA
promoter, thereby regulating the rate of ribosome biogenesis. Because
ribosomes are required for protein synthesis, proliferating cells
invest much energy in ribosome generation (reviewed in Reference 3).
Without concomitant synthesis, proliferating cells would only become
progressively smaller. Thus, growth involves increasing numbers of
cells with maintenance of proper cell size, and IGF-IR is involved in
regulating both these processes.
Adda Grimberg, MD
References - (linked to  )
- Vincent AM, Feldman EL. Growth Horm Igf Res 2002;12:193-7.
- Dupont J, Pierre A, Froment P, Moreau C. Horm Metab Res 2003;35:740-50.
- Moss T. Curr Opin Genet Develop 2004;14:210-7.
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Current GGH - Vol. 24 No. 1
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