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HIGHLIGHTS
NATURE REVIEWS | CANCER VOLUME 1 | OCTOBER 2001 | 3
HIGHLIGHTS ADVISORS
ANTON BERNSNETHERLANDS CANCERINSTITUTE, AMSTERDAM, THE NETHERLANDS
PETER CARMELIETCATHOLIC UNIVERSITY LEUVEN,LEUVEN, BELGIUM
RON DEPINHOHARVARD MEDICAL SCHOOL,BOSTON, MA, USA
STEPHEN W. FESIKABBOTT LABORATORIES,ABBOTT PARK, IL, USA
ELI GILBOA DUKE UNIVERSITY MEDICALCENTER, DURHAM, NC, USA
TOMAS LINDAHLIMPERIAL CANCER RESEARCHFUND, HERTFORDSHIRE, UK
LANCE LIOTTANATIONAL CANCER INSTITUTE,BETHESDA, MD, USA
JANET D. ROWLEYUNIVERSITY OF CHICAGOMEDICAL CENTER, CHICAGO,IL, USA
DAVID SIDRANSKYJOHNS HOPKINS UNIVERSITYSCHOOL OF MEDICINE, BALTIMORE, MD, USA
JÜRG TSCHOPPUNIVERSITY OF LAUSANNE,EPALINGES, SWITZERLAND
BERT VOGELSTEIN JOHNS HOPKINS ONCOLOGYCENTER, BALTIMORE, MD, USA
ROBERT A. WEINBERGWHITEHEAD INSTITUTE FORBIOMEDICAL RESEARCH, CAMBRIDGE, MA, USA
SAVIO WOOMOUNT SINAI SCHOOL OFMEDICINE, NEW YORK, NY, USA
Most cancer researchers would agreethat the distinction between anoncogene and a tumour suppressoris crystal clear: oncogenes areunleashed by dominant, gain-of-function mutations, whereas bothalleles of a tumour suppressor mustsuffer a loss of function for tumori-genesis to occur. Could any genecombine these properties? ZhongqiuZhang and colleagues report in theSeptember issue of Nature Geneticsthat Kras2 — one of the most fre-quently activated oncogenes — cancross-dress as a tumour suppressor.
The question was why, if Kras2really is a dominant onco-gene, do somet u m o u r swith acti-v a t i n gKras2
mutations lose their other Kras2 allele?The authors decided to search for theanswer in chemically induced lungtumours in mice, which invariablycontain oncogenic Kras2 mutationsthat lock its product, the small GTP-binding protein K-Ras, into its active,GTP-bound form.
A comparison of Kras2+/– micewith Kras2+/+ mice revealed that,remarkably, the Kras2+/– mice devel-oped more, larger lung tumoursthan Kras2+/+ mice after a singleintraperitoneal injection of the car-cinogen urethane. Furthermore, thetumours in Kras2+/– mice were moreinvasive, less differentiated adeno-carcinomas, whereas those in
Kras2+/+ mice were lessadvanced (adenomas),indicating that the sec-ond Kras2 allele blockstumour progression as
well as initiation.Similar results wereobtained withanother carcino-gen, methyl-nitrosurea.
All of thesetumours con-
tained activat-ing mutations in
Kras2, so the presenceof a wild-type Kras2allele seemed to beblocking the ability ofthe mutated allele todrive tumour initiationand progression. Sureenough, in two cell lines
with activating Kras2 mutations,transfection with wild-type Kras2inhibited cell growth by 80–90%.But how? The mitogen-activatedprotein kinase Erk is a well-knowndownstream target of activated Ras,but wild-type Kras2 blocked theactivation of Erk in one of these celltypes, indicating that prevention ofErk activation is one means bywhich wild-type Kras2 can exert itstumour-suppressor effect. However,cell growth was inhibited evenwhen transfected wild-type Kras2did not inhibit Erk, so other mecha-nisms of Ras-mediated tumoursuppression must exist.
So, wild-type Kras2, which isalmost always GDP-bound, seems tohave a restraining effect on its onco-genic alter ego, but how it does this isnot clear. Does GDP-bound K-Rashave its own effectors that drive dif-ferentiation of pulmonary epitheli-um? The less differentiated tumoursin the Kras2+/– mice would indicatethat they do. If so, we can imagine aconstant battle in the tumour cellbetween the mild manners of Rasthe tumour suppressor, and thewanton ways of Ras the oncoprotein.
Cath Brooksbank
References and linksORIGINAL RESEARCH PAPER Zhang, Z. et al.Wildtype Kras2 can inhibit lung carcinogenesis inmice. Nature Genet. 29, 25–33 (2001)FURTHER READING Pfeifer, G. P. A new verdictfor an old convict. Nature Genet. 29, 3–4 (2001)WEB SITESGenes and disease: the Ras oncogene:http://www.ncbi.nlm.nih.gov/disease/Ras.htmlMing You’s lab:http://www.cancergenetics.med.ohio-state.edu/FacultyYou.html
Dr Jekyll and Mr Hyde
O N C O G E N E S
MGM (Courtesy of the Kobal Collection).
© 2001 Macmillan Magazines Ltd