Transcript Fibroblast Growth Factor 3 (FGF3) int

Fibroblast Growth Factor 3
(FGF3)
int-2
Brandon Williams
3/25/03
OBJECTIVES
• Biochemical Information
• Normal Function in Mouse Ear
Development
• Breast Cancer and FGF3
EASY FACTS
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22 FGFs in vertebrates
FGF3: Chromosome 11 (humans)
Fgf3: Chromosome 7 (mice)
Are secreted polypeptides
Use tyrosine kinase receptors for signaling
Proto-oncogene
FUNCTIONS
• Cell proliferation, migration, and
differentiation during embryonic
development
• Tissue repair, injury response in adults
• Angiogenesis
FGF and Tyrosine Kinases
• FGFs bind to heparan sulfate and tyrosine
kinase receptors (FGFRs)
• FGF binds to heparan sulfate
• FGF/heparan sulfate dimer binds to a
FGFR
• Complexes form dimers
• Signal transduction
FGFRs
• 7 prototypes from 4 genes
• 2 or 3 immunoglobulin-like extracellular
domains
• Heparan sulfate binding domain
• Activated through autophosphorylation
• Signaling pathway includes Ras, Raf,
SOS, etc.
Receptor Dimerization
FGFRs
What Does FGF3 do in a wt
Mouse?
• Mouse lives (viable)
• Inner ear problems
• Skeletal problems (tail)
Mouse Ear Development
• FGF3 was thought to induce inner ear
development
• McKay et al. showed that FGF3 is required
for correct development of inner ear, not
induction of otic placode
Kreisler Mutant Mice
• Cannot be maintained as completely
homozygous line (females do not breed
and repeated outcrossing is needed to
produce breeding stud males)
• Develop a otic placode etc.
• Inner ear is mutant
FGF Expression
Breast Cancer Numbers
• Most frequent cancer among women,
other than skin cancer
• 203,500 new cases per year in U.S.
• 40,000 die each year
• 1 in 8 women
• 5% attributed to mutated BRCA1
FGF3 and Breast Cancer
• Mouse Mammary Tumor Virus (MMTV)
• Insertion of MMTV activates several genes
including FGF3 that have been associated
with breast cancer
• Mixed results
• Cyclin D is closely linked to FGF3