PMID- 12368906
OWN - NLM
STAT- MEDLINE
DCOM- 20030123
LR  - 20091119
IS  - 1078-8956 (Print)
IS  - 1078-8956 (Linking)
VI  - 8
IP  - 11
DP  - 2002 Nov
TI  - Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in 
      rhabdomyosarcomagenesis.
PG  - 1276-80
AB  - Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet 
      molecular events associated with the genesis and progression of this potentially 
      fatal disease are largely unknown. For the molecules and pathways that have been 
      implicated, genetic validation has been impeded by lack of a mouse model of RMS. 
      Here we show that simultaneous loss of Ink4a/Arf function and disruption of c-Met 
      signaling in Ink4a/Arf(-/-) mice transgenic for hepatocyte growth factor/scatter 
      factor (HGF/SF) induces RMS with extremely high penetrance and short latency. In 
      cultured myoblasts, c-Met activation and Ink4a/Arf loss suppress myogenesis in an 
      additive fashion. Our data indicate that human c-MET and INK4a/ARF, situated at 
      the nexus of pathways regulating myogenic growth and differentiation, represent 
      critical targets in RMS pathogenesis. The marked synergism in mice between 
      aberrant c-Met signaling and Ink4a/Arf inactivation, lesions individually 
      implicated in human RMS, suggests a therapeutic combination to combat this 
      devastating childhood cancer.
FAU - Sharp, Richard
AU  - Sharp R
AD  - Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland, 
      USA.
FAU - Recio, Juan A
AU  - Recio JA
FAU - Jhappan, Chamelli
AU  - Jhappan C
FAU - Otsuka, Toshiyuki
AU  - Otsuka T
FAU - Liu, Shiquan
AU  - Liu S
FAU - Yu, Yanlin
AU  - Yu Y
FAU - Liu, Wenjing
AU  - Liu W
FAU - Anver, Miriam
AU  - Anver M
FAU - Navid, Fariba
AU  - Navid F
FAU - Helman, Lee J
AU  - Helman LJ
FAU - DePinho, Ronald A
AU  - DePinho RA
FAU - Merlino, Glenn
AU  - Merlino G
LA  - eng
GR  - U01CA84313-04/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20021007
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Tumor Suppressor Protein p14ARF)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
EIN - Nat Med. 2003 Jan;9(1):146.
CIN - Nat Med. 2002 Nov;8(11):1200-1. PMID: 12411939
MH  - Animals
MH  - Cells, Cultured
MH  - Cyclin-Dependent Kinase Inhibitor p16/*genetics
MH  - Hepatocyte Growth Factor/*metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Transgenic
MH  - Proto-Oncogene Proteins c-met/metabolism
MH  - Rhabdomyosarcoma/genetics/*metabolism
MH  - *Signal Transduction
MH  - Soft Tissue Neoplasms/genetics/*metabolism
MH  - Tumor Suppressor Protein p14ARF/*genetics
EDAT- 2002/10/09 04:00
MHDA- 2003/01/24 04:00
CRDT- 2002/10/09 04:00
PHST- 2002/07/16 00:00 [received]
PHST- 2002/09/17 00:00 [accepted]
PHST- 2002/10/09 04:00 [pubmed]
PHST- 2003/01/24 04:00 [medline]
PHST- 2002/10/09 04:00 [entrez]
AID - nm787 [pii]
AID - 10.1038/nm787 [doi]
PST - ppublish
SO  - Nat Med. 2002 Nov;8(11):1276-80. doi: 10.1038/nm787. Epub 2002 Oct 7.