Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN...
-
Upload
lester-welch -
Category
Documents
-
view
215 -
download
1
Transcript of Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN...
![Page 1: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/1.jpg)
Not division… But growth
![Page 2: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/2.jpg)
Cells must growCells must grow
![Page 3: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/3.jpg)
![Page 4: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/4.jpg)
PI3K
GFR
Akt
Rheb
Ras
mTOR
Tuberin/Hamartin
PTEN
Neurofibromin
Tuberous sclerosis complex
Neurofibromatosis type 1 (NF1)
Cowden Syndrome Lhermitte-Duclos
disease
S6KeIF4E
NPMARF p68
![Page 5: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/5.jpg)
Thinking about translationThinking about translation
![Page 6: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/6.jpg)
The forgotten translation…top The forgotten translation…top mmRNARNAss
Terminal Oligo Pyrimidine tracts: 5’-CTTTCTTCTC…
![Page 7: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/7.jpg)
RaptormLST8
mTOR
RictormLST8
mTOR
FKBP12
Actin cytoskeleton
Ribosomal biogenesis
Protein translation
Rapamycin
![Page 8: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/8.jpg)
![Page 9: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/9.jpg)
![Page 10: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/10.jpg)
![Page 11: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/11.jpg)
PDK1
PTENMutations 5%LOH ~30%
Akt Akt2 amplified < 5%
S6K1 Amplified ~10% (17q23)
PIK3CA Mutations in ~25% overallGene amplification < 10%
(~25%)(~25%)(~45%)(<7%)
ER+
HER2+
ER+/HER2+
ER-/HER2-
?
mTOR
NPM ?
4E-BP1?
eIf4e?
The growth pathway is subject to enormous mutation ratesThe growth pathway is subject to enormous mutation rates
![Page 12: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/12.jpg)
PIK3CA mutations in ~25% of breast cancers
(~25%)(~25%)(~45%)(<7%)
ER+
HER2+
ER+/HER2+
ER-/HER2-
~275 samples from ER+ patients undergoing Letrozole therapy
Developed sequencing pipeline for Exons 1,6,7,9,20 with GSC
Goal 1: Attack the genotypeGoal 1: Attack the genotype
Figure adapted from Cancer Res 65: 2554
Hypothesis: pik3ca mutations render tumors resistant to ER- and HER2-targeted therapies
![Page 13: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/13.jpg)
CONSERVATION OF NUCLEOLAR STRUCTURE/FUNCTION CONSERVATION OF NUCLEOLAR STRUCTURE/FUNCTION
RESIDENTS DRIFTERS
NPM/B23NCL/C23
FibrillarinCdc14B
Nop5/SikBop1
R-proteinshnRNP’s
TCOF1NUMA1
Ki67p19ARF
Cdc14ATERTWRNING1PP1
SMN1UBF
Mdm2MdmX
Cyclin Ep53
DKC1PES1BLM
MammalsMammals(~450)(~450)
drosophiladrosophila
YeastYeast(~39)(~39)zebrafishzebrafish
xenopusxenopus
![Page 14: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/14.jpg)
D. Trere (2000) D. Trere (2000) MicronMicron 3131:127-131:127-131
UNIFORM AgNOR & SAPA SCORING METHODUNIFORM AgNOR & SAPA SCORING METHOD
![Page 15: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/15.jpg)
RIBOSOMAL GENES AND THE NUCLEOLUSRIBOSOMAL GENES AND THE NUCLEOLUS
FIVE rGENE CLUSTERSFIVE rGENE CLUSTERSCHR. 13, 14, 15, 21, 22CHR. 13, 14, 15, 21, 22OVER 400 TANDEM REPEATSOVER 400 TANDEM REPEATS~47 KB REPEAT ELEMENT~47 KB REPEAT ELEMENTYIELDS 13KB TRANSCRIPTYIELDS 13KB TRANSCRIPT
![Page 16: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/16.jpg)
Processing is everythingProcessing is everything
![Page 17: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/17.jpg)
rrrna modificationsrna modifications
![Page 18: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/18.jpg)
Suppressing transcription…first important clueSuppressing transcription…first important clue
![Page 19: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/19.jpg)
Lots of steps to mess with…Lots of steps to mess with…
![Page 20: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/20.jpg)
Myc sends us another clue…Myc sends us another clue…
![Page 21: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/21.jpg)
S6K
eIF4E
ProteinSynthesis
NPM
40
60 40
6040
60
RibosomalExport
rRNATranscription
CYTOPLASM
NUCLEOLUS
TIF1A
RNA Pol I
40
60
mTOR
![Page 22: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/22.jpg)
Nuclear export
nucleus
cytosoplasm
AA
AA
AA
AA
-3’
5’60S 40S
mTOR
S6K
NPM
nucleolus
Nucleophosmin acts in a late Nucleophosmin acts in a late rrRNA stageRNA stage
![Page 23: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/23.jpg)
Nucleophosmin is mutated in human cancersNucleophosmin is mutated in human cancers
![Page 24: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/24.jpg)
nucleus
cytosoplasm
nucleolus
60S40S
60S40S
AA
AA
AA
AA
-3’
5’
PI3K
S6K
NPM
rRNA Export
Polysomes
Proteinsynthesis
This mutant is hyperactive in This mutant is hyperactive in rrRNA exportRNA export
![Page 25: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/25.jpg)
…The pathway can be addictive
mTORC2
Rac1
NPM
rRNA Export
Rapamycin
Neurofibromin K-Ras
Polysomes
Proteins
None NoneLY LYRap Rap
Nf1+/+ Nf1-/-
Tubulin
S6P
Neurofibromin controls the growth pathwayNeurofibromin controls the growth pathway
![Page 26: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/26.jpg)
PI3K
CELL SURVIVAL CELL GROWTH CELL PROLIFERATION
Nucleolar Integrity
ARF/p53
Rapamycin
ARF
mTOR
S6K
NPM
rRNA Export
Polysomes
Protein synthesis
The pathway must have checks in placeThe pathway must have checks in place
![Page 27: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/27.jpg)
THE THE INK4A-ARFINK4A-ARF LOCUS LOCUS
FibrosarcomasLymphomas
Gliomas
Melanomas FibrosarcomasLymphomas
Gliomas
1 1 2 3
Ink4a/ARF
Cyclin D-Cdk4 Mdm2
Rb p53
?
![Page 28: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/28.jpg)
Pol III
5S
Pol I
5.8S18S28S
NUCLEOLUS NUCLEOPLASM
5S---rpL5---NPM
ARF
60S
NUCLEAREXPORT
Synchronized ribosome exportSynchronized ribosome export
![Page 29: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/29.jpg)
Layers of potential targets…Layers of potential targets…
RTK
Ras
p85p110
PDK1 AKT
PTENP P
PP
MDM2
IKK
eNOS
TSC1/2
GSK3
FOXO
Myc mTOR
Cyclin D
p53
NF-B
p27kip1
Rhebcdk4
eIF4ENPM
28S
18S
5.8S5S
ARF S6K 4E-BP1
28S 18S 5.8S
![Page 30: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/30.jpg)
![Page 31: Not division…But growth. Cells must grow PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis.](https://reader035.fdocuments.in/reader035/viewer/2022070408/56649e675503460f94b626ce/html5/thumbnails/31.jpg)