Proviral tagging in E mu-myc transgenic mice lacking the Pim-1 proto-oncogene leads to compensatory activation of Pim-2.
The Pim-1 proto-oncogene is one of the most potent collaborators of the myc proto-oncogenes in inducing lymphomagenesis in mice. Contrary to the profound effects when overexpressed in vivo, Pim-1-deficient mice showed only subtle phenotypic alterations, which could indicate the presence of redundantly acting genes. In line with this, a PCR-based screen has led to the identification of a closely homologous gene, Pim-2. The X-linked Pim-2 gene is 53% identical to Pim-1 at the amino acid level and shares substrate preference and the usage of non-AUG initiation codons with Pim-1. We have used these data to test whether the strong synergistic interaction between Pim-1 and c-myc can be utilized to gain access to Pim-1 compensatory pathways. We reasoned that, upon proviral tagging in compound mutant mice (E mu-myc/Pim-1-/- mice), the selective advantage of cells carrying provirally activated genes, that act downstream from or parallel to Pim-1, would increase. We show here that this is the case. A dramatic increase (from 15 to 80%) was found in the frequency of proviral activation of the Pim-2 gene. These data show that the described strategy of 'complementation tagging' represents a powerful new tool to identify components of pathways involved in processes as complex as multistep tumorigenesis.
van der Lugt
N M
NM
Department of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam.
Domen
J
J
Verhoeven
E
E
Linders
K
K
van der Gulden
H
H
Allen
J
J
Berns
A
A
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D016259:Genes, myc; D008223:Lymphoma / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1; D011519:Proto-Oncogenes; D011533:Proviruses / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
D018076:DNA, Complementary; C094167:Pim2 protein, mouse; D011518:Proto-Oncogene Proteins; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1