Translational control of the proteome : Relevance to cancer

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Translational control of the proteome Relevance
to cancer
Proteomics 2001 , 1 , 1191 - 1199

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• 2001 - 23173
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Contents

• 1. Introduction to translational control
• 2. eIF4E, a key factor or a model molecule for
  deregulated translation in cancer?
• 3. Expression of other translation factors in
  human cancers
• 4. Translation infidelity in tumorigenesis
• 5. Application of genomic and proteomic
  technologies to the study of translational
  control

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1. Introduction to translational control

• growth factors, cytokines, hormones
• Cell proliferation ?
• Translation rate ?

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eIF4E

• Binds to the cap structure at the 5 end of the
  mRNA
• Importance of eIF4E for Growth control
• (i) Expression of antisense RNA against eIF4E
  mRNA results in lengthened cell division times
  and diminished translation rates
• (ii) Ectopic expression of the eIF4E-binding
  proteins (4E-BPs), inhibitors of eIF4E activity,
  reduces cell growth

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eIF2?

• Phosphorylation of eIF2? leads to reduced levels
  of ternary complex (Met-tRNAi/eIF2/GTP) and an
  inhibition of translation.
• PKR ( eIF2? phosphorylation ) overexpression
• ? apoptosis and fibroblasts in HeLa cells

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Selective Translational Control

• Mechanisms that target ligands to individual
  mRNAs
• The differential sensitivity of mRNAs to subtle
  changes in the activity of components of the
  translation machinery (5untranslated region of
  mRNAs )

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2. eIF4E, a key factor or a model molecule for
deregulated translation in cancer?

• overexpression of eIF4E in NIH-3T3 fibroblastic
  cells ? rapid proliferation and malignant
  transformation
• eIF4E abundance in breast , head , neck squamous
  cell and colon carcinomas
• tumor marker for breast cancers ( might be
  suitable )
• Tumor invasion and metastasis
• eIF4E is normal in lung and pancreas carcinomas

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eIF4E
the vascular endothelial growth factor (VEGF) the
basic fibroblast growth factor (FGF-2) Powerful
tumor angiogenic factors
cyclin D1 ( growth regulatory )
ornithine decarboxylase ( malignancy-related
proteins)
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3. Expression of other translation factors in
human cancers

• eIF2?
• PKR ( tumor suppressor )
• negative mutant forms of PKR
• ? malignant transformation
• mutation at eIF2? unique phosphorylation ?
  malignant transformation

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4. Translation infidelity in tumorigenesis

• translation efficiency ? 5untranslated region of
  mRNAs
• Mdm2 gene ( potential transforming activity )
• differ only in 5 leaders of Mdm2 mRNA
• The long form mdm2 mRNA contains two upstream
  ORFs and is inefficiently translated

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5. Application of genomic and proteomic
technologies to the study of translational control

• Microarray ( 220 human tumors )
• 41 ovarian tumors
• 57 lung carcinomas grades 1 and 3
• 50 colon tumors
• 24 oligodendrogliomas grades 3 and 2
• 40 astrocytomas grades 4 and 1
• 8 pancreas tumors
• 2-DE
• phosphorylation status of eIF4E, eIF4G, eIF4B,
  eIF3 and eIF2

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eIF4E P
eIF4E P
eIF4E
eIF4E
eIF4E P
eIF4E