Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomas.
Acceleration of lymphomagenesis in oncogene-bearing transgenic mice by slow-transforming retroviruses has proven a valuable tool in identifying cooperating oncogenes. We have modified this protocol to search for genes that can collaborate effectively with the transgene in later stages of tumor development. Propagation of tumors induced by Moloney murine leukemia virus (M-MuLV) in E mu-Pim1 or H2-K-myc transgenic mice by transplantation to syngeneic hosts permitted proviral tagging of 'progression' genes. Molecular cloning of common proviral insertion sites that were detected preferentially in transplanted tumors led to the identification of a novel gene, designated Frat1. The initial selection for integrations near Frat1 occurs in primary tumor cells that have already acquired proviruses in other common insertion sites, yielding primary lymphomas that contain only a minor fraction of tumor cells with an activated Frat1 allele. Transplantation of such primary lymphomas allows for a further expansion of tumor cell clones carrying a proviral insertion near Frat1, resulting in detectable Frat1 rearrangements in 17% of the transplanted E mu-Pim1 tumors and 30% of the transplanted H2-K-myc tumors, respectively. We have cloned and sequenced both the mouse Frat1 gene and its human counterpart. The proteins encoded by Frat1 and FRAT1 are highly homologous and their functions are thus far unknown. Tumor cell lines with high expression of Myc and Pim1 acquired an additional selective advantage in vivo upon infection with a Frat1-IRES-lacZ retrovirus, thus underscoring the role of Frat1 in tumor progression, and the ability of Frat1 to collaborate with Pim1 and Myc in lymphomagenesis.
Jonkers
J
J
Division of Molecular Genetics (H-4), The Netherlands Cancer Institute, Amsterdam.
Korswagen
H C
HC
Acton
D
D
Breuer
M
M
Berns
A
A
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D003001:Cloning, Molecular; D015342:DNA Probes / Q000235:genetics; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D008979:Moloney murine leukemia virus / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000821:virology; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000235:genetics*; D015183:Restriction Mapping; D016415:Sequence Alignment; D017421:Sequence Analysis; D013194:Staining and Labeling; D014161:Transduction, Genetic / Q000235:genetics
D015342:DNA Probes; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas