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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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Presentation Transcript
slide1

Not division…

But growth

slide4

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

slide6

The forgotten translation…top mRNAs

Terminal Oligo Pyrimidine tracts: 5’-CTTTCTTCTC…

slide7

Raptor

mLST8

Ribosomal biogenesis

FKBP12

mTOR

Rapamycin

Protein translation

Rictor

mLST8

Actin cytoskeleton

mTOR

slide11

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

?

slide12

~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

slide13

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

slide14

UNIFORM AgNOR & SAPA SCORING METHOD

D. Trere (2000) Micron31:127-131

slide15

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

slide21

40

40

40

40

60

60

60

60

CYTOPLASM

rRNA

Transcription

S6K

Protein

Synthesis

TIF1A

mTOR

eIF4E

RNA Pol I

NPM

Ribosomal

Export

NUCLEOLUS

slide22

mTOR

S6K

NPM

AAAAAAAA-3’

60S

40S

5’

Nucleophosmin acts in a late rRNA stage

cytosoplasm

nucleus

nucleolus

Nuclear export

slide24

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

slide25

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

slide26

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

slide27

THE INK4A-ARF LOCUS

Ink4a/ARF

?

Cyclin D-Cdk4

Mdm2

Rb

p53

1b

1a

2

3

Fibrosarcomas

Lymphomas

Gliomas

Fibrosarcomas

Lymphomas

Gliomas

Melanomas

slide28

Pol I

Pol III

18S

5.8S

28S

5S

Synchronized ribosome export

NUCLEOLUS

NUCLEOPLASM

5S---rpL5---NPM

NUCLEAR

EXPORT

ARF

60S

slide29

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…