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Tumor Suppressors / Cell cycle Eldad Zacksenaus MGY-425 March 1 st , 3 rd , 2010

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Tumor Suppressors / Cell cycle Eldad Zacksenaus MGY-425 March 1 st , 3 rd , 2010. The Hallmarks of Cancer. Principles of cancer therapy: oncogene and non-oncogene addiction Luo J, Solimini NL, Elledge SJ. Cell. 2009 Mar 6;136(5):823-37. . Oncogenes are activated in human cancer and

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slide1

Tumor Suppressors /

Cell cycle

Eldad Zacksenaus

MGY-425

March 1st, 3rd, 2010

slide2

The Hallmarks of Cancer

Principles of cancer therapy: oncogene and non-oncogene addiction

Luo J, Solimini NL, Elledge SJ.

Cell. 2009 Mar 6;136(5):823-37.

slide3

Oncogenes are activated in human cancer and

promote hallmarks of cancer

Tumor suppressors (TS) are lost in human cancer and

inhibit hallmarks of cancer

slide4

For example, evasion of apoptosis:

  • • Bcl-2 is a survival factor (It inhibits mitochondrial outer
  • membrane permeabilization (MOMP) and the release of
  • cytochrome c, which is required for caspase activation and cell death).
  • - Bcl-2 is amplified in cancer, hence an oncogene
  • • p53 is an anti-survival factor (among other functions, it transcriptionally
  • activates Bax which induces MOMP and cell death)
  • p53 is lost in cancer hence a TS (however most mutations in p53 are
  • not null but dominant negative mutations that also inhibit p63 - hence
  • oncogenic)
  • • The TS RB inhibits cell proliferation - but also apoptosis. Its loss leads
  • to ectopic proliferation (oncogenic) but also so apoptosis (tumor
  • suppression).
slide5

Tumor

suppressor

Hallmark

Function

Evading apoptosis p53 Induces apoptotic genes (Bax)

Self-sufficiency in Pten Dephosphorylates PIP3, counteracting PI3K

growth signal pRb Inhibits E2F

Insensitivity to anti- SMAD4 Induces CDK4/6 inhibitor p16ink4a in response to TGF

growth signals p16ink4a Inhibits cyclins

DNA damage stress ATM Induces p53 and DNA repair machinery

Mitotic stress LATS2 Inhibits MDM2 (activates p53)

Metabolic stress/hypoxia VHL E3 ligase for HIF-1

slide6

Signaling, Oncogenes, tumor-suppressors

and non-oncogene addiction

signal

+

Oncogene

Tumor suppressor

-

Negative regulator that is not mutated/lost in cancer

-

Positive regulator that is not activated in cancer

Non-oncogenic addiction

+

slide7

For example: The phosphatidylinositol 3-kinase (PI3K) signaling cascade

G protein

couple receptor

Receptor tyrosine

kinase

RTK, +, onc Ras, +, onc

PI3K, +, onc

Pten, - , TS

Akt, +, onc

MDM2, +, onc

P53, - , TS/onc

GSK3, -

B-cat, +

Myc, +, onc

CyclinD1, +, onc

TSC, -, TS

+

cyclin D1

-catenin

myc

Courtney, K. D. et al. J Clin Oncol; 28:1075-1083 2010

slide8

The landscape of somatic copy-number alteration across human cancers

High-resolution Affimetric analysis (250K array containing probes for 238,270 single nucleotode polymorphisms

(SNPs) for somatic copy-number alterations (SCNAs) from 3,131 cancer specimens

Ink4-Arf

Beroukhim R., et al Nature463, 899-905 (18 February 2010)

slide9

Notes:

• On average: 24 gains and 18 losses

• Most frequent - Myc amplification and Cdkn2A/B (p16ink4a and Arf)

deletion.

• At least 10 known tumor suppressors not identified by this analysis -

Brca2, Fbxw7, Nf2, Ptch1, Smarcb1, Stk11, Sufu, Vhl, Wt1, and Wtx

- Some of these are specific to cancer types (e.g. Nf2, Wt1)

- Other primarily suffer arm-level deletions (e.g. Brca2)

- Some TS genes undergo point mutations not deletions

slide10

To cycle or not

R.A. Weinberg Biology of Cancer 2006. Figure 8.1 The Biology of Cancer (© Garland Science 2007)

slide11

Examples of checkpoints in the cell cycle

Figure 8.4 The Biology of Cancer (© Garland Science 2007)

slide12

The restriction point

Figure 8.6 The Biology of Cancer (© Garland Science 2007)

slide13

Phosphorylation of the retinoblastoma gene product is modulated during

the cell cycle and cellular differentiation

Stages during the cell

cycle when pRb in

under-phosphorylated

Chen PL, Scully P, Shew JY, Wang JY, Lee WH. Cell. 1989 Sep 22;58(6):1193-8.

Karen Buchkovich, Linda A. Duffy and Ed Harlow Cell. 1989 Sep 22;58(6):1097-105.

James A. DeCaprio, John W. Ludlow, Dennis Lynch, Yusuke Furukawa, James Griffin, Helen Piwnica-Worms, Chun-Ming Huang

and David M. Livingston 1989 Cell ;58(6):1085-95.

slide14

The retinoblastoma gene product regulates progression through the

G1 phase of the cell cycle.

Micro-injection of Rb

protein during this

period blocks entry

into S phase

Goodrich DW, Wang NP, Qian YW, Lee EY, Lee WH.Cell. 1991 18;67(2):293-302.

Goodrich DW, Wang NP, Qian YW, Lee EY, Lee WH.Cell. 1991 67(2):293-302.

slide15

D and E type cyclins, which are active in early and late G1, sequentially

phosphorylate pRb (Cyclin A/B maintain pRb phosphorylation later on)

Figure 8.8 The Biology of Cancer (© Garland Science 2007)

slide16

Cell cycle-dependent fluctuations in cyclin B levels

Figure 8.9 The Biology of Cancer (© Garland Science 2007)

slide17

Fluctuation of cyclin levels during the cell cycle

Figure 8.10 The Biology of Cancer (© Garland Science 2007)

slide19

Control of cyclin levels during the cell cycle

CDC2 = Cdk1 is sufficient to drive the mammalian cell cycle - CDK4/6/3/2 are not essential for cell proliferation and early embryogenesis - till midgestation)

Santamar D, Barrie C, Cerqueira A, Hunt S, Tardy C, Newton K, Ceres JF, Dubus P, Malumbres M, Barbacid M.

Nature. 2007 Aug 16;448(7155):811-5.

Figure 8.12 The Biology of Cancer (© Garland Science 2007)

slide20

Schematic structure of pRb and CDK phospho-acceptor sites

Amino acid

S

S

T

T

T

T

S

S

S

S

S

S

S

S

T

T

Location

224

243

246

350

364

367

561

601

605

773

781

788

800

804

814

819

S

S

T

T

T

T

S

S

S

SSSSSTT

pRb

N

A

B

C

Spacer

Exon23

788

800/804

814/819

G1 to S transition

G0 to G1

transition

Binding to LxCxE

containing factors

+

Constitutive interaction with E2F1 suppression of Rat1 cell proliferation

slide21

Two-dimensional tryptic phosphopeptide analysis of pRB phosphorylated by different CDKs.

Zarkowska T , Mittnacht S J. Biol. Chem. 1997;272:12738-12746

©1997 by American Society for Biochemistry and Molecular Biology

slide22

Localization and assignment of CDK2-cyclin A phosphorylated residues using phosphoamino acid analysis and phosphorylation of pRB subfragments.

Zarkowska T , Mittnacht S J. Biol. Chem. 1997;272:12738-12746

©1997 by American Society for Biochemistry and Molecular Biology

slide23

Identification of a CDK4-cyclin D1 specific phosphorylation site by mutagenesis.

Zarkowska T , Mittnacht S J. Biol. Chem. 1997;272:12738-12746

©1997 by American Society for Biochemistry and Molecular Biology

slide25

E2F1, 2 and 3a are major targets of pRb

Figure 8.23d The Biology of Cancer (© Garland Science 2007)

slide27

LxCxE binding

LxCxE motif

Figure 8.24a The Biology of Cancer (© Garland Science 2007)

slide29

Actions of CDK inhibitors

Figure 8.13a The Biology of Cancer (© Garland Science 2007)

slide30

Control of cell cycle progression by

TGF-

Figure 8.14a The Biology of Cancer (© Garland Science 2007)

slide32

Regulation of p21 localization

Figure 8.15b The Biology of Cancer (© Garland Science 2007)

slide33

Regulation of p27 localization

AKT phosphorylates p27 on T157, causing it to localize to the cytoplasm

Nat Med 2002;8:1145–52; Nat Med 2002;8:1136–44

Figure 8.15c The Biology of Cancer (© Garland Science 2007)

slide34

Nuclear p27 accumulation in tumors inversely correlates with pAKT

Figure 8.16a The Biology of Cancer (© Garland Science 2007)

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