Welcome to Scribd, the world's digital library. Read, publish, and share books and documents. See more
Download
Standard view
Full view
of .
Look up keyword
Like this
0Activity
0 of .
Results for:
No results containing your search query
P. 1
128 Davoli AnnRevCellDevBiol 2010

128 Davoli AnnRevCellDevBiol 2010

Ratings: (0)|Views: 0|Likes:
Published by Terry Fletcher

More info:

Categories:Types, Research, Science
Published by: Terry Fletcher on Dec 10, 2012
Copyright:Attribution Non-commercial

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as PDF, TXT or read online from Scribd
See more
See less

12/10/2012

pdf

text

original

 
 The Causes and Consequencesof Polyploidy in NormalDevelopment and Cancer
 Teresa Davoli and Titia de Lange
Laboratory for Cell Biology and Genetics, The Rockefeller University, New York,NY 10065; email: delange@mail.rockefeller.edu Annu. Rev. Cell Dev. Biol. 2011. 27:585–610First published online as a Review in Advance on July 21, 2011 The
Annual Review of Cell and Developmental Biology
is online at cellbio.annualreviews.org This article’s doi:10.1146/annurev-cellbio-092910-154234Copyright c
2011 by Annual Reviews. All rights reserved1081-0706/11/1110-0585$20.00
Keywords
telomere, tetraploidy, aneuploidy 
 Abstract 
 Although nearly all mammalian species are diploid, whole-genome du-plications occur in select mammalian tissues as part of normal devel-opment. Such programmed polyploidization involves changes in theregulatory pathways that normally maintain the diploid state of themammalian genome. Unscheduled whole-genome duplications, whichlead primarily to tetraploid cells, also take place in a substantial fractionof human tumors and have been proposed to constitute an important step in the development of cancer aneuploidy. The origins of thesepolyploidization events and their consequences for tumor progressionare explored in this review.
585
   A  n  n  u .   R  e  v .   C  e   l   l   D  e  v .   B   i  o   l .   2   0   1   1 .   2   7  :   5   8   5  -   6   1   0 .   D  o  w  n   l  o  a   d  e   d   f  r  o  m   w  w  w .  a  n  n  u  a   l  r  e  v   i  e  w  s .  o  r  g   b  y   R  o  c   k  e   f  e   l   l  e  r   U  n   i  v  e  r  s   i   t  y  o  n   0   2   /   1   0   /   1   2 .   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .
Click here
for quick links toAnnual Reviews content online,including:• Other articles in this volume• Top cited articles• Top downloaded articles• Our comprehensive search
Further
ANNUALREVIEWS
 
 Tetraploidy:
a formof polyploidy; the stateof having four sets of chromosomes (4N)
E2F:
transcriptionfactor that promotesS-phase entry and isnegatively regulated by Rb
 Anaphase-promoting complex/cyclosome(APC/C):
an E3ubiquitin ligase boundto the activator Cdc20in metaphase and toCdh1 in late anaphaseand G1
Contents
 MAINTENANCE OF THEDIPLOID MAMMALIANGENOME ........................ 586 TETRAPLOIDIZATION INNORMAL DEVELOPMENT..... 588 TETRAPLOIDIZATION WITH AGING AND STRESS............ 591CHROMOSOME INSTABILITY IN HUMAN CANCER ........... 591EVIDENCE FOR  TETRAPLOIDIZATION INHUMAN CANCER............... 592CAUSES OF TETRAPLOIDY INCANCER......................... 594ROLE OF P53 IN CULLING  TETRAPLOID CLONES......... 598CONSEQUENCES OF TETRAPLOIDY IN CANCER.... 599 TIMING OF TETRAPLOIDIZATIONDURING TUMORIGENESIS.... 599FUTURE PERSPECTIVES.......... 602
 MAINTENANCE OF THEDIPLOID MAMMALIAN GENOME
 Mammals are diploid. The only exception tothis rule is the red vizcacha rat (
Tympanoctomys barrerae
) and its close relatives, which aretetraploid (Gallardo et al. 1999). In othermammals, tetraploidy causes early lethality and spontaneous abortion or resorption of theembryo (Creasy et al. 1976, Kaufman 1991).In contrast, tetraploid species are widespreadin plants and fairly frequent in insects,crustaceans, fish, amphibians, and reptiles(Masterson 1994, Otto & Whitton 2000).Polyploidization has been proposed to haveoccurred twice early in vertebrate evolution(Ohno 1970, Van de Peer et al. 2009). The re-sulting paleopolyploid state of the mammaliangenome can explain the multiple paralogsof many genes (e.g., Hox gene cluster; Ras,Rb, and E2F genes) (Schughart et al. 1989).Nonetheless, each mammalian somatic cellgenerally contains exactly two copies of theautosomal chromosomes (the maternal andpaternal homologs). The diploid state of mammalian somaticcells is guarded by control mechanisms that act throughout the cell cycle to prevent theoccurrence and/or proliferation of cells withdeviant DNA contents (
Figure 1
). The cyclin-dependent kinases (Cdks) and their cyclinsubunits regulate key protein phosphorylationevents such that DNA replication and mitosisalternate, driving the cell cycle forward; theinitiation of DNA replication is controlledby a system that prevents rereplication; andtwo types of checkpoints [the DNA damagecheckpoints and the spindle assembly check-point (SAC)] ensure the integrity of the diploidgenome and the correct separation of newly replicated sister chromatids. These controlsare highlighted in
Figure 1
and discussedbriefly below.Chromosome nondisjunction is preventedby regulatory pathways, generally known as er-ror correction pathways, that promote correct kinetochore-microtubuleattachments(forare- viewseeMusacchio&Salmon2007).TheSACexerts an additional level of control on the cellcycle in that it blocks anaphase until all chro-mosomes have achieved bioriented attachment to the mitotic spindle (
Figure 1
). The dissolu-tion of sister chromatids in anaphase requiresactivation of the APC/C (anaphase-promotingcomplex/cyclosome), an ubiquitin ligase that together with either Cdc20 or Cdh1 targetsmitotic proteins for degradation by the pro-teasome. A signal emanating from unattachedkinetochores inhibits APC/C-Cdc20. Once allchromosomesarecorrectlyalignedonthespin-dle,theSACisswitchedoff,andAPC/C-Cdc20becomes active, which leads to degradation of securin. With securin gone, separase can cleavethe cohesin that holds the sister chromatidstogether, and one copy of each duplicatedchromosome is segregated to each daughtercell. After mitosis, a regulatory pathway controlsthe initiation of DNA replication such that 
586 Davol
·
de Lange
   A  n  n  u .   R  e  v .   C  e   l   l   D  e  v .   B   i  o   l .   2   0   1   1 .   2   7  :   5   8   5  -   6   1   0 .   D  o  w  n   l  o  a   d  e   d   f  r  o  m   w  w  w .  a  n  n  u  a   l  r  e  v   i  e  w  s .  o  r  g   b  y   R  o  c   k  e   f  e   l   l  e  r   U  n   i  v  e  r  s   i   t  y  o  n   0   2   /   1   0   /   1   2 .   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .
 
  G   2
M
 G      1      
       S
 
  G   2
Cdk1/CycBCdk2/CycE,A
Prophase Metaphase Anaphase CytokinesisAPC/C-Cdc20Unattached kinetochore
Mitosis (M)
 
Incomplete replicationDNA damage
G2/M
ATM/ATRCdk1/CycBCdc25CChk1/2Pre-RCOrigin
G1
Cdt1Origin licensingDNA damageATM/ATRCdk2/CycE,ACdc25A p21p53-P
G1/S
Pre-RCCdk2/CycE,A
S phase
Cdt1One round of DNA replicationGeminin
Figure 1
How mammalian somatic cells maintain a diploid genome. The schematic outlines the normal somatic cell cycle and highlights thethree main mechanisms by which the diploid genome is kept intact: assurance of correct chromosome segregation in mitosis, regulationof DNA replication, and the DNA damage checkpoints. Abbreviations: APC/C, anaphase-promoting complex/cyclosome; ATM/ATR,ataxia telangiectasia mutated/ATM and Rad3-related; Cdk, cyclin-dependent kinase; Chk, checkpoint kinase; Cyc, cyclin; pre-RC,prereplication complex.
www.annualreviews.org 
Polyploidy in Cancer 587
   A  n  n  u .   R  e  v .   C  e   l   l   D  e  v .   B   i  o   l .   2   0   1   1 .   2   7  :   5   8   5  -   6   1   0 .   D  o  w  n   l  o  a   d  e   d   f  r  o  m   w  w  w .  a  n  n  u  a   l  r  e  v   i  e  w  s .  o  r  g   b  y   R  o  c   k  e   f  e   l   l  e  r   U  n   i  v  e  r  s   i   t  y  o  n   0   2   /   1   0   /   1   2 .   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .

You're Reading a Free Preview

Download
scribd
/*********** DO NOT ALTER ANYTHING BELOW THIS LINE ! ************/ var s_code=s.t();if(s_code)document.write(s_code)//-->