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

Slide1 l.jpg
Download
1 / 34

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

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

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.

Download Presentation

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

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Slide1 l.jpg

Tumor Suppressors /

Cell cycle

Eldad Zacksenaus

MGY-425

March 1st, 3rd, 2010


Slide2 l.jpg

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 l.jpg

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 l.jpg

  • 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 l.jpg

Tumor

suppressor

Hallmark

Function

Evading apoptosis p53Induces apoptotic genes (Bax)

Self-sufficiency in PtenDephosphorylates PIP3, counteracting PI3K

growth signal pRb Inhibits E2F

Insensitivity to anti- SMAD4Induces CDK4/6 inhibitor p16ink4a in response to TGF

growth signals p16ink4a Inhibits cyclins

DNA damage stress ATMInduces p53 and DNA repair machinery

Mitotic stress LATS2Inhibits MDM2 (activates p53)

Metabolic stress/hypoxia VHLE3 ligase for HIF-1


Slide6 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

To cycle or not

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


Slide11 l.jpg

Examples of checkpoints in the cell cycle

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


Slide12 l.jpg

The restriction point

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


Slide13 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

Cell cycle-dependent fluctuations in cyclin B levels

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


Slide17 l.jpg

Fluctuation of cyclin levels during the cell cycle

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


Slide18 l.jpg

Cell cycle-dependent phosphorylation of pRb


Slide19 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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


Slide24 l.jpg

Summary of pRB residues phosphorylated by individual CDKs


Slide25 l.jpg

E2F1, 2 and 3a are major targets of pRb

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


Slide26 l.jpg

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


Slide27 l.jpg

LxCxE binding

LxCxE motif

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


Slide28 l.jpg

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


Slide29 l.jpg

Actions of CDK inhibitors

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


Slide30 l.jpg

Control of cell cycle progression by

TGF-

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


Slide31 l.jpg

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


Slide32 l.jpg

Regulation of p21 localization

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


Slide33 l.jpg

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 l.jpg

Nuclear p27 accumulation in tumors inversely correlates with pAKT

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


  • Login