IGF-1
description
Transcript of IGF-1
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IGF-1Insulin-Like Growth Factor 1Matthew Klinka
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BackgroundPrimarily produced in the liverHowever is also a paracrine
hormone◦Present in many cell types in a wide
range of tissue types.Typically bound to proteins when
both intra or extracellular◦98% of IGF-1 is protein bound◦IGFBP-3 most common
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http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=20049
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ProductionProduction of IGF-1 is linked to
dietary protein intake◦Especially casein◦Protein free diet can result in IGF-1
deficiencyMade in response to growth
hormone signalling
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FunctionAnabolic Hormone
◦IGF-1 triggers growth until adulthood◦After adulthood triggers hypertrophy
in skeletal muscleRegulates kidney function and
growth
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ReceptorReceptor is IGF1R
◦“Insulin-like growth factor 1 receptorTyrosine Kinase receptor
◦Dimeric◦Two sets of Alpha & Beta subunits◦320 Kda◦Member of the Insulin receptor
family◦Beta subunits contain the catalytic
tyrosine residues
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IGF-2 BindingIGF1R may also bind IGF-2Key differences:
◦IGF-2 functions primarily in fetal development During gestation aids neural
development◦IGF-1 functions in adults
During gestation deals with physical development
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http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=68828
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Primary ResultIGF1R triggering often results in
cell proliferation or growthHowever still a cell specific
response◦Ie: may trigger growth in size of an
adult’s skeletal muscle cells, or may trigger growth and subsequent division of embryonic cells
◦May even trigger growth (hypertrophy) of heart muscle cells
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Role in reproductionIGF1R plays a role in the
development of limb buds in an embryo
IGF1R serves to facilitate lactation in pregnant and nursing females◦Differentiates breast cells into duct
and glandular tissue◦Prevents apoptosis of duct and
glandular tissue during pregnancy and nursing
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CancerBecause of it’s anti-apoptotic
action, IGF1R may contribute to some cancers◦Prostate◦Breast◦Cervical
All of the above have been observed to contain cells with heightened levels of IGF1R
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CraniosynostosisPremature ossification of sutures
in an infant cranium◦Results in oddly shaped skull and in
most cases brain damage if not corrected
Caused by a number of different single nucleotide polymorphisms in IGF1R
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Secondary ReceptorIGF-1 Can also bind insulin
receptor◦Also a tyrosine Kinase receptor◦Much lower binding affinity than
IGF1R◦IGF-1 binds at 10% of the rate of
insulin◦May form a heterodimer with IGF1R
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RegulationIn serum may be bound by
certain IGFBPs◦IGF-1 has a higher affinity for some
of these than it does for its receptor◦IGF1R may be targeted with tyrosine
kinase inhibitors◦miRNA thought to play a role in
regulation as well
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Laron Syndrome
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Laron SyndromeAutosomal recessiveResults from low levels or low
efficacy of IGF-1◦Most cases are due to a lack of GH
receptor◦Some due to mutation in genes
coding for IGF-1 or IGF1R
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SymptomsNormal GH levelsVery low IGF-1 levelsShort statureProminent foreheadObesity in the trunk of the bodyLack of response to GH therapy
◦Typically used to treat other forms of dwarfism
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TreatmentSynthetic IGF-1Must be taken before pubertyNot effective if there are other
mutations further along the signaling pathway
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Cancer, Diabetes, and agingInterestingly, people with Laron
syndrome are nearly immune to cancer and diabetes.◦Two theories for cancer protection
1. IGF-1 has anti-apoptotic function Reduced IGF-1 results in more normal apoptosis
2. Lack of IGF-1 somehow results in more protection from oxidative DNA damage
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Diabetes protectionLaron syndrome sufferers have
high insulin sensitivity despite being obese◦Most likely reason is because IGF-1
can bind insulin receptor◦In the absence of a competitor, a
smaller amount of insulin can have great effect
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AgingIn mice, mutations reducing IGF-
1 levels resulted in longer lifespans on average◦In nematodes IGF-1 deficiency
resulted in doubling of lifespanMechanism is not understood
◦Unknown if this property occurs in humans Only ~300 people with Laron Syndrome
worldwide Difficult to establish a baseline because
incidence of accidental death is relatively common
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http://www.biocarta.com/pathfiles/h_ghrelinPathway.asp
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http://www.biocarta.com/pathfiles/h_igf1pathway.asp