Disease relevance of Frat1

• The Frat1 proto-oncogene was first identified as a gene contributing to tumor progression in T-cell lymphomas induced by retroviral insertional mutagenesis with the Moloney murine leukemia virus [1].
• 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 [2].
• Overexpression of Frat1 in transgenic mice leads to glomerulosclerosis and nephrotic syndrome, and provides direct evidence for the involvement of Frat1 in lymphoma progression [3].

High impact information on Frat1

• Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomas [2].
• This has yielded a series of oncogenes that could be assigned to different complementation groups in transformation: the myc, Pim, Bmi1, and Frat1 complementation groups [4].
• Frat1 might exert its activity by impairing the kinase activity of Gsk3beta, which is involved in the degradation of beta-catenin [4].
• The addition of Wnt3a or overexpression of constitutively active truncated LRP5 (LRP5C) induces Frat1 recruitment to the cell membrane [5].
• We demonstrate here that LRP5/Frat1 interaction is involved in beta-catenin nuclear translocation and TCF-1 transcriptional activation [5].

Biological context of Frat1

• Frat2 protein accumulates to higher levels upon transfection into 293T cells than either Frat1 or Frat3 [1].
• Frat1 and Frat2 are juxtaposed on chromosome 19 in a chromosomal organization conserved between man and mouse [1].
• We show that Frat1 and Frat2 are phosphorylated, which is the first evidence that these proteins are subject to posttranslational modification [1].
• In an attempt to gain more insight into the function of Frat1, we have generated Frat1-deficient mice in which most of the coding domain was replaced by a promoterless beta-galactosidase reporter gene [6].
• The overlapping expression patterns of Frat1 and Frat3 during murine embryogenesis suggest that the apparent dispensability of Frat1 for proper development may be due to the presence of a second mouse gene encoding a functional Frat protein [6].

Anatomical context of Frat1

• To substantiate this notion we have generated transgenic mice that overexpress Frat1 in various organs, including lymphoid tissues [3].

Other interactions of Frat1

• This analysis revealed that Lvis1 maps between two previously identified viral insertion sites, His2 and Frat1, and does not cosegregate with known gene markers [7].
• Together these data suggest that Frat may be the endogenous factor that targets GSK-3 for nuclear export [8].
• Axin, which has been shown to interact with LRP5 and to be recruited to the membrane through this interaction, was found to co-immunoprecipitate with Frat1 and LRP5 [5].
• 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 [3].

Analytical, diagnostic and therapeutic context of Frat1

• Molecular cloning of common proviral insertion sites that were detected preferentially in transplanted tumors led to the identification of a novel gene, designated Frat1 [2].
• 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 [2].

References