Overexpression of Frat1 in transgenic mice leads to glomerulosclerosis and nephrotic syndrome, and provides direct evidence for the involvement of Frat1 in lymphoma progression.
The proto-oncogene Frat1 was originally identified as a common site of proviral insertion in transplanted tumors of Moloney murine leukemia virus (M-MuLV)-infected Emu-Pim1 transgenic mice. Contrary to most common insertion sites implicated in mouse T cell lymphomagenesis, retroviral insertional mutagenesis of Frat1 constitutes a relatively late event in M-MuLV-induced tumor development, suggesting that proviral activation of Frat1 contributes to progression of T cell lymphomas rather than their genesis. To substantiate this notion we have generated transgenic mice that overexpress Frat1 in various organs, including lymphoid tissues. Frat1 transgenic mice develop focal glomerulosclerosis and a nephrotic syndrome, but they do not exhibit an increased incidence of spontaneous lymphomas. Conversely, these mice are highly susceptible to M-MuLV-induced lymphomagenesis, and Frat1/Pim1 bitransgenic animals develop lymphomas with increased frequency compared to Pim1 transgenic littermates. These data support a role for Frat1 in tumor progression.
Jonkers
J
J
Division of Molecular Genetics and Center of Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Weening
J J
JJ
van der Valk
M
M
Bobeldijk
R
R
Berns
A
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016026:Bone Marrow Transplantation; D002352:Carrier Proteins; D018450:Disease Progression; D004742:Enhancer Elements, Genetic; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D008223:Lymphoma / Q000235:genetics* / Q000821:virology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008979:Moloney murine leukemia virus / Q000472:pathogenicity; D009363:Neoplasm Proteins; D009404:Nephrotic Syndrome / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C491818:Frat1 protein, mouse; D007143:Immunoglobulin Heavy Chains; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1