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The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64

Oncogene volume 19, pages 3182–3192 (2000)Cite this article

Abstract

The Mom1 (Modifier of Min-1) region of distal chromosome 4 was identified during a screen for polymorphic modifiers of intestinal tumorigenesis in ApcMin/+ mice. Here, we demonstrate that the Mom1AKR allele consists of two genetic components. These include the secretory phospholipase Pla2g2a, whose candidacy as a Mom1 resistance modifier has now been tested with several transgenic lines. A second region, distal to Pla2g2a, has also been identified using fine structure recombinants. Pla2g2aAKR transgenic mice demonstrate a modest resistance to tumorigenesis in the small intestine and a very robust resistance in the large intestine. Moreover, the tumor resistance in the colon of Pla2g2aAKR animals is dosage-dependent, a finding that is consistent with our observation that Pla2g2a is expressed in goblet cells. By contrast, mice carrying the distal Mom1 modifier demonstrate a modest tumor resistance that is confined to the small intestine. Thus, the phenotypes of these two modifier loci are complementary, both in their quantitative and regional effects. The additive effects and tight linkage of these modifiers may have been necessary for the initial identification of the Mom1 region.

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Abbreviations

APC/Apc :

adenomatous polyposis coli gene in humans/mice

Min/Min:

Multiple intestinal neoplasia [note: Min is also used in place of ApcMin/+ and Min is used to indicate mice and tumors]

B6:

C57BL/6J

Mom1 :

Modifier of Min-1

LOH:

loss-of-heterozygosity

AKR:

AKR/J

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Acknowledgements

We thank Cheri Pasch for PCR genotyping, Harlene Edwards and Jane Weeks for preparation of tissue samples for histological analysis, Linda Clipson for assistance in the production of this manuscript, Kevin Haigis for testing chromosome 4 markers, Ilse Riegel for careful reading and editing of the manuscript, Kim Severson, Matt Wiluth, and Jesse Waggoner for DNA isolation, and Jen Triemstra and the McArdle animal care staff for help in animal husbandry. In addition, we wish to thank Kathy Helmuth and the staff at the UW-Biotechnology Center Transgenic Animal Facility for their expertise in making the Pla2g2aAKR transgenic mice, and Rita Mulherkar for supplying us with Pla2g2a antiserum. Jay Tischfield and Michelle Winstead generously shared with us the unpublished sequences for Pla2g2c and Pla2gV, with which we were able to map these genes relative to recombinant breakpoints. Alexandra Shedlovsky and Kevin Haigis provided valuable critiques of this manuscript. This study was supported by National Institute of Health (NIH) grants to McArdle Laboratory (CA07075), to William F Dove (CA50585, CA63677), to Eric S Lander (HG00098, and the Whitehead Institute), and Robert T Cormier, a predoctoral training grant (CA09135). In addition we thank the American Cancer Society (PF-4217) and the NIH (CA77946) for postdoctoral fellowships to Richard B Halberg, and the NIH for a postdoctoral fellowship to Andrea Bilger (CA72243).

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  1. Robert T Cormier and Andrea Bilger: RT Cormier and A Bilger contributed equally.

Authors and Affiliations

  1. McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, 53706, Wisconsin, WI, USA

    Robert T Cormier, Andrea Bilger, Amy J Lillich, Richard B Halberg, Karen A Gould, Natalie Borenstein & William F Dove

  2. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, 02142, Massachusetts, MA, USA

    Karen H Hong & Eric S Lander

  3. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, MA, USA

    Karen H Hong & Eric S Lander

  4. Laboratory of Genetics, University of Wisconsin, Madison, 53706, Wisconsin, WI, USA

    Karen A Gould & William F Dove

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Cormier, R., Bilger, A., Lillich, A. et al. The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64. Oncogene 19, 3182–3192 (2000). https://doi.org/10.1038/sj.onc.1203646

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