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Not division…

Not division…. But growth. Cells must grow. GFR. Neurofibromin. Neurofibromatosis type 1 (NF1). Ras. PI3K. PTEN. Tuberin/ Hamartin. Cowden Syndrome Lhermitte-Duclos disease. Akt. Tuberous sclerosis complex. mTOR. Rheb. eIF4E. S6K. NPM. ARF. p68. Thinking about translation.

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Not division…

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  1. Not division… But growth

  2. Cells must grow

  3. GFR Neurofibromin Neurofibromatosis type 1 (NF1) Ras PI3K PTEN Tuberin/ Hamartin Cowden Syndrome Lhermitte-Duclos disease Akt Tuberous sclerosis complex mTOR Rheb eIF4E S6K NPM ARF p68

  4. Thinking about translation

  5. The forgotten translation…top mRNAs Terminal Oligo Pyrimidine tracts: 5’-CTTTCTTCTC…

  6. Raptor mLST8 Ribosomal biogenesis FKBP12 mTOR Rapamycin Protein translation Rictor mLST8 Actin cytoskeleton mTOR

  7. PIK3CA Mutations in ~25% overall Gene amplification < 10% Mutations 5% PTEN ER+ HER2+ ER+/HER2+ ER-/HER2- (~25%) (~25%) (~45%) (<7%) LOH ~30% Akt Akt2 amplified < 5% mTOR 4E-BP1 S6K1 ? Amplified ~10% (17q23) eIf4e NPM ? ? The growth pathway is subject to enormous mutation rates PDK1 ?

  8. ~275 samples from ER+ patients undergoing Letrozole therapy Developed sequencing pipeline for Exons 1,6,7,9,20 with GSC PIK3CA mutations in ~25% of breast cancers ER+ HER2+ ER+/HER2+ ER-/HER2- (~25%) (~25%) (~45%) (<7%) Goal 1: Attack the genotype Hypothesis: pik3ca mutations render tumors resistant to ER- and HER2-targeted therapies Figure adapted from Cancer Res65: 2554

  9. drosophila xenopus Mammals (~450) zebrafish Yeast (~39) CONSERVATION OF NUCLEOLAR STRUCTURE/FUNCTION RESIDENTS DRIFTERS NPM/B23 NCL/C23 Fibrillarin Cdc14B Nop5/Sik Bop1 R-proteins hnRNP’s TCOF1 NUMA1 Ki67 p19ARF Cdc14A TERT WRN ING1 PP1 SMN1 UBF Mdm2 MdmX Cyclin E p53 DKC1 PES1 BLM

  10. UNIFORM AgNOR & SAPA SCORING METHOD D. Trere (2000) Micron31:127-131

  11. RIBOSOMAL GENES AND THE NUCLEOLUS FIVE rGENE CLUSTERS CHR. 13, 14, 15, 21, 22 OVER 400 TANDEM REPEATS ~47 KB REPEAT ELEMENT YIELDS 13KB TRANSCRIPT

  12. Processing is everything

  13. rrna modifications

  14. Suppressing transcription…first important clue

  15. Lots of steps to mess with…

  16. Myc sends us another clue…

  17. 40 40 40 40 60 60 60 60 CYTOPLASM rRNA Transcription S6K Protein Synthesis TIF1A mTOR eIF4E RNA Pol I NPM Ribosomal Export NUCLEOLUS

  18. mTOR S6K NPM AAAAAAAA-3’ 60S 40S 5’ Nucleophosmin acts in a late rRNA stage cytosoplasm nucleus nucleolus Nuclear export

  19. Nucleophosmin is mutated in human cancers

  20. 60S 40S AAAAAAAA-3’ 5’ This mutant is hyperactive in rRNA export PI3K cytosoplasm S6K nucleus NPM rRNA Export Polysomes 60S 40S Protein synthesis nucleolus

  21. Neurofibromin controls the growth pathway Neurofibromin K-Ras …The pathway can be addictive None LY Rap None LY Rap Rapamycin mTORC2 S6 P Tubulin Rac1 Nf1+/+ Nf1-/- NPM rRNA Export Polysomes Proteins

  22. Rapamycin ARF/p53 Nucleolar Integrity ARF The pathway must have checks in place PI3K CELL SURVIVAL CELL GROWTH CELL PROLIFERATION mTOR S6K NPM rRNA Export Polysomes Protein synthesis

  23. THE INK4A-ARF LOCUS Ink4a/ARF ? Cyclin D-Cdk4 Mdm2 Rb p53 1b 1a 2 3 Fibrosarcomas Lymphomas Gliomas Fibrosarcomas Lymphomas Gliomas Melanomas

  24. Pol I Pol III 18S 5.8S 28S 5S Synchronized ribosome export NUCLEOLUS NUCLEOPLASM 5S---rpL5---NPM NUCLEAR EXPORT ARF 60S

  25. RTK P AKT P PDK1 Ras p27kip1 p110 P p85 P PTEN FOXO eNOS MDM2 TSC1/2 p53 GSK3b IKK Cyclin D Rheb NF-kB cdk4 Myc mTOR 28S 18S 5.8S ARF S6K 4E-BP1 28S 5.8S NPM 5S eIF4E 18S Layers of potential targets…

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