3 Park Square Milton Park Abingdon, OX14 4RN UK
new SeCOnD eDitiOn
PraiSe fOr the firSt eDitiOn Of
the BiOLOGY Of CanCer
BY rOBert a. weinBerG:
“There is no comparable text in cancer biology…” — Nature
“the Biology of Cancer is no doubt the definitive statement on its topic today.” — SCieNCe
“Here, at last, we have a definitive textbook specifically devoted to the molecular and cell biology of cancer.” — BioSCieNCe eduCatioN
“Overall, this is a remarkable achievement that is by far the most comprehensive coverage of this field available.” —timeS HigHer eduCatioN SupplemeNt
294
and C 8: pRb Chapter
lC the Cel ontrol of 1
(A)
ycle Clo
COntentS
ck (B) BrdU
Kip1
7
p2 7Kip n by p2 DAPI ates positio itotic st 8.18 Im ent Figure Kip2 of post-m velopm 7 t The de ntiation en and p5 pm e differe develo during depends on th imposition es the Kip1 and of tissu lls and p27 yonic ce Kip1 of embr itotic states by p27 1 m Jagged ssion of s of post-2 suppre mors ha of its Kip . While of es tu p57 any typ the role m d, in te is en levels ogenes docum th ly pa de er been wi 7Kip2 , in canc . p5 strated cousin, ment demon Kip2 s to be develop cells p57 remain rebellar atally as h of ce rs postn a post-mitotic (A) Muc cu oc of age mals 7 days ter into rebellar en in mam d an iate of ce course different ferating ring the se, proli state. Du ent in the mou h their m throug develop idine tected n be de bromodeoxyur are cells ca ey ration of alog; th incorpo idine an al day 7 by a thym at y (BrdU), at postn ing an antibod d here reveale uorescence us aining DNA nt ofl -co un been imm BrdU Kip1 have gnizes 7 co p2 re tagged that els of The lev a fluorescence- me (green). of the sa 1 by use Kip izes it in gauged recogn rent, p27 at th y ased antibod d). As is appa have ce (re is e lls that th of section th of ag g that th tes in ce one mon plete 1 mon dicatin m accumula g (above). By co ence in n. is t tin tle evid or progressio lopmen Kip1 (red) ve prolifera de r ere is lit m 7 rebella low, th ps of tu els of p2 roughout be ste d lev c age, ce e ile ifi th th ta ec , and levels t, as de le in sp (below) ese cells at high lopmen s a critical ro tained hold th er deve ay are main , ostensibly to The Notch to canc l of control pl od . (B) ve B) adultho tic state other le ure 6.29 Fig st-mito d e po (se a ing y in ck lineate g pathwa y tissues in blo tic early de e signalin ito an ing its cl through thes ed in m lls into post-m ing , includ is involv es here trate advances llular signals e of ce thereby allow gl nc an n. l tra ra tio es the en states, m seve e extrace through the prolifera at orch ed e th fro th iat e tiv to Ks nt cl ac cy CD back differe the ntinue the cell progress ly how the ins and traced lls to co ocular lens of e viewed ases; the cycl and to can be ise such ce vances tive cell cycle to reveal prec We have ph veloping gestation), th these ad , and M ac es In the de fail .5 of d) induc G1, S, G2 d the fact that enter into the ns, however, (day 17 sed1 (re mouse pressor, an gg tio ; re to Ja es ll al rip d suppre l. as ce an ion ph tumor ese desc olecular leve de the Notch lig of a transcript in turn Rb Th ua . e rs oblaste th n ich int ga n of the m that pe of retin expressio shown), wh 7Kip2 (light isolatio n (R) po uted at enesis Table (not by the restrictio nsition is exec e pathog r tumors (see ed n of p5Kip2 expression, th id Herp2 sio in ov es des a t tra lved s expr 7 othe n was pr it enco R-poin represse ptor, ca are invo as as well as ssing p5 puzzle rent that riously pRb suppre which tch rece to this rcinom ions of blue). By acting via a No an actively me appa va lution in The so ive vers all-cell lung ca 1986, it beca otein, called many of the 1, ct ain fe ing m de re Jagged , in lop pr lls of that ce the deve sor gene rcomas, and sm was isolated t 105 kD. This Cell the cells ensure te until e, sa gene form, in cycle modulation of pRb abou ting sta riate siz tomas, fective r the Rb of a mass of prolifera s to an approp sion is then ncert t in a de on afte es n in co 7.1). So oprotein nt, or presen postlens grow p57Kip2 expr orylatio essentially se pose a phosph r ab ph im ich ea os to be wh by cl it r nu ing b is afte oes ph und to vealed ed, allow nuclei are re cally, pRby (hypophosunderg , was fo m types. CDK2thand which areifiremoved Sidebar 8.3RB Phosphorylation fro at itCDC2, or permitt tumor of CDK veal ed e spec . Cell at ed or , above ed to te yl M (A m or sta e. v. na e). re a classceof cl phosphatases called osphCDC25A, trance in cy moleculesabalso ove- controls theirwactivity mitotic nes De ark blu ith pRb h th eir ll eakly ph ues after en a much PI dye (d S. Xie et al., Ge teAn entsplaced sy additional level pe mes wthe -C. effects of these en- ) on control onroug -B and the DA coWhile , ex of rim lls th ine resid low cour sel. , F. Zindy in G0; be ylated reon Initial of cells nce of cecan ce ine G cell cycle clock machinery bells are zymes and G2 are poorly phorunderT. Uziel 2667, 2005; be M.F. Rousthe e va an 1,dS,th os nc ad e ph va en rin d 6– se yperthey play ith ad with th t, pRb l. 19:265 et, F. Zindy, an ofmber of stood, or it ylisatclear ylated wh l nu ed (hthat ncert wcritical phormodifications Cell. Bio traced to the covalent e R poin rg osphin triggering s in co a smalMore ely ph unphos themselves. of A. Fo , J. et al., Mol. rough th e cell cycle. the CDK molecules roles G2/M th transition: residue the ed) on Jia passed during of th e extensiv d thcyclin orylat ve lingered reoninB,e whichha B, from 7247, 2007.) mes specifically, ph CDKs must be phosphorhas ainder G2 by the enzym 6– d beco rine an 19). Once cells hout the rem ped off an se ; 27:723 G of 1 ylated at specific amino acidr residues in in the cytoplasm, moves into the nu-
how s reveal protein e al onco cl 8.5 Vir ugh the cell cy thro
pRb blo
n cks adva
ce
Thoroughly updated and incorporating the most important advances in the fast-growing field of cancer biology, The Biology of Cancer, Second Edition, maintains all of its hallmark features admired by students, instructors, researchers, and clinicians around the world.
The Biology of Cancer is a textbook for students studying the molecular and cellular bases of cancer at the undergraduate, graduate, and medical school levels. The principles of cancer biology are presented in an organized, cogent, and in-depth manner. The clarity of writing, supported by an extensive full-color art program and numerous pedagogical features, makes the book accessible and engaging. The information unfolds through the presentation of key experiments that give readers a sense of discovery and provide insights into the conceptual foundation underlying modern cancer biology.
The tumor microenvironment Metastatic dissemination Tumor immunology Cancer stem cells The epithelial-mesenchymal transition • Multi-step tumorigenesis • Invasion and metastasis
• Mutation of cancer cell genomes • Greatly expanded treatment of traditional therapy • Epigenetic contributions • MicroRNA involvement • The Warburg effect
Besides its value as a textbook, The Biology of Cancer is a useful reference for individuals working in biomedical laboratories and for clinical professionals. Every copy of the book comes with an updated “Pathways in Human Cancer” poster and a DVD-ROM containing the book’s art program, a selection of movies, audio file mini-lectures, Supplementary Sidebars, and a Media Guide.
d throug
phosphorylation
295
• Concept Headings
are strip
• Sidebars Contain additional information or anecdotes pertinent to the discussion that are set aside so as not to disrupt the logical flow of the main text.
The fact that pRb hyperphosphorylation occurs in concert with passage through the R point provided the first hint that this protein is the molecular governor of the R-point transition. An additional, critical clue came from the discovery in 1988 of physical interactions between DNA tumor virus–encoded oncoproteins and pRb. Recall that DNA tumor viruses are able to transform cells and do so through the use of virusencoded oncoproteins. Unlike the oncoproteins of RNA tumor viruses such as RSV, the DNA tumor viruses employ oncoproteins that have little if any resemblance to the proteins that exist naturally within uninfected cells (see Sections 3.4 and 3.6).
• Synopsis and prospects This section places the topic of that chapter into a larger perspective while providing a summary, and a link to later chapters. In these sections the author speculates about future research.
CDC2
dephosphorylation extent of pRb phosphorylation M G2
A
G1
CDC2
hypophosphorylation D CDK4/6
R point S
hyperphosphorylation A
CDK2 E
CDK2
Figure 8.19 Cell cycle–dependent phosphorylation of pRb The phosphorylation state of pRb (red circle) is closely coordinated with cell cycle advance. As cells pass through the M/G1 transition, virtually all of the existing phosphate groups are stripped off pRb, leaving it in an unphosphorylated configuration. As cells progress through G1, a single phosphate group is attached as any one of 14 different phosphorylation sites (by cyclin D-CDK4/6 complexes), yielding hypophosphorylated pRb. However, when cells pass through the restriction (R) point, cyclin E–CDK2 complexes phosphorylate pRb on at least 12 more sites, placing it in a hyperphosphorylated state. Throughout the remainder of the cell cycle, the extent of pRb phosphorylation remains constant until cells enter into M phase.
• key Concepts A summary of the chapter’s essential points, in list form, to aid in review.
StuDent & inStruCtOr reSOurCeS • • • • • • • •
j u N e 2013 • 960 pa g e S • 584 i l l u S t r at i o N S
13. Dialogue Replaces Monologue: Heterotypic Interactions and the Biology of Angiogenesis 14. Moving Out: Invasion and Metastasis 15. Crowd Control: Tumor Immunology and Immunotherapy 16. The Rational Treatment of Cancer A sample chapter and detailed table of contents are available at www.garlandscience.com/tboc2.
• thought Questions
These introduce each section of the text and help the student focus on, and review, key ideas.
termed protein phosphatase type 1 (PP1). This removal of phosphate groups, in turn, sets the stage for the next cell cycle and thus for a new cycle of pRb phosphorylation.
B
7. Tumor Suppressor Genes 8. pRb and Control of the Cell Cycle Clock 9. p53 and Apoptosis: Master Guardian and Executioner 10. Eternal Life: Cell Immortalization and Tumorigenesis 11. Multi-step Tumorigenesis 12. Maintenance of Genomic Integrity and the Development of Cancer
PeDaGOGiCaL featureS
(Fthe intAt pRbG2/M transition; larger(see Figure rylate order to be active 8.7). before ps onthe the R po ou hosphocleusatjust hyperp phos ph e gr through phosphorylations same time, inhibitory phosphorylations of a threonine and a remains the lly residues itosis,be usua of other amino acid tyrosine residue that are located near mmust it ex lls After ce removed. The stimulatory phosphorylathe ATP-binding site of CDC2 and intions are imparted by a serine/threonine hibit kinase activity are then removed kinase termed CAK (for CDK-activating by CDC25 phosphatases, enabling the kinase). CAK itself is a cyclin–CDK comrapid activation of B–CDC2 complexes plex, which phosphorylates the activathat proceed to trigger entrance into M tion loops (often called T-loops) of CDKs phase. CDC25A and CDC25B are over(see Figure 8.7), causing them to swing expressed in some cancers, and there out of the way of the catalytic clefts of is evidence from mouse models of canthese serine/threonine kinases. cer development that their overexpresEqually important are the effects of sion may lead to acceleration of tumor inhibitory phosphorylations affecting development.
The new Second Edition has been comprehensively revised and updated to include major advances in cancer biology over the past six years. Updates include current information on: • • • • •
igure 8.
numbe
1. The Biology and Genetics of Cells and Organisms 2. The Nature of Cancer 3. Tumor Viruses 4. Cellular Oncogenes 5. Growth Factors, Receptors, and Cancer 6. Cytoplasmic Signaling Circuitry Programs Many of the Traits of Cancer
Figures in PowerPoint® and JPEG formats. Movies with narration cover selected topics. Audio files of mini-lectures by the author. Online flashcards and glossary. “Pathways in Human Cancer” poster. Supplementary Sidebars. Media Guide. A Question Bank containing 10 to 15 questions for each chapter is available for instructors only.
Digital resources can be found on the DVD-ROM included in the book, or on the Instructor and Student sections of the Garland Science website:
www.garlandscience.com/tboc2.
Please also visit the website to order an examination copy of the book for consideration on your course.
pa p e r B a C k • 978 - 0 - 8153 - 4220 - 5 • £55.00
Designed to provide review, analysis, and to provoke discussion.
• references An extensive list of pertinent articles and books for those who want to delve deeper into a topic.
• techniques Summary The major techniques referred to throughout the text are indexed separately.
• glossary Defines terms in bold and italics within the text.
• list of acronyms and abbreviations A handy reference that helps readers navigate the nomenclature of the primary research literature.
aBOut the authOr dr. robert a. Weinberg is a founding member of the Whitehead Institute for Biomedical Research. He is the Daniel K. Ludwig Professor for Cancer Research and the American Cancer Society Research Professor at the Massachusetts Institute of Technology (MIT). Dr. Weinberg is an internationally recognized authority on the genetic basis of human cancer and was awarded the U.S. National Medal of Science in 1997.
H a r d C o v e r • 978 - 0 - 8153 - 4219 - 9 • £105.00