Met proto-oncogene product is overexpressed in tumors of p53-deficient mice and tumors of Li-Fraumeni patients.
Inappropriate expression of Met, the receptor for hepatocyte growth factor/scatter factor, has been implicated in sarcomagenesis via an autocrine mechanism. Sarcomas occur at high frequency in individuals with Li-Fraumeni syndrome as well as in p53-deficient mice. Here we show that these tumors express high levels of Met. Moreover, late passage fibroblast cell lines established from p53-deficient animals overexpress Met and can be tumorigenic in athymic nude mice, suggesting that progression occurs in vitro. The tumor explants display increased hepatocyte growth factor/scatter factor expression and Met turnover, indicating that autocrine Met activation contributes to tumor progression. Thus, the loss of wild-type p53 appears to greatly enhance the opportunity for inappropriate Met expression. Loss of p53 function does not by itself cause transformation, but inappropriate Met expression may be an important factor in sarcomagenesis.
Rong
S
S
ABL Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702, USA.
Donehower
L A
LA
Hansen
M F
MF
Strong
L
L
Tainsky
M
M
Jeffers
M
M
Resau
J H
JH
Hudson
E
E
Tsarfaty
I
I
Vande Woude
G F
GF
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D012513:Sarcoma, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D014443:Tyrosine / Q000378:metabolism
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016159:Tumor Suppressor Protein p53; D014443:Tyrosine; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases