Somatic Apc mutations are selected upon their capacity to inactivate the β-catenin downregulating activity
Ron Smits
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
R. Smits, N. Hofland, and W. Edelmann contributed equally to the work presented in the manuscript.
Search for more papers by this authorNandy Hofland
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
R. Smits, N. Hofland, and W. Edelmann contributed equally to the work presented in the manuscript.
Search for more papers by this authorWinfried Edelmann
Department of Cell Biology, Albert Einstein College of Medicine of Yeshiva University, New York, New York
R. Smits, N. Hofland, and W. Edelmann contributed equally to the work presented in the manuscript.
Search for more papers by this authorMarjan Geugien
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorShantie Jagmohan-Changur
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorCristina Albuquerque
Laboratório de Biologia Molecular, CIPM, Lisbon, Portugal
Search for more papers by this authorCor Breukel
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorRaju Kucherlapati
Department of Molecular Genetics, Albert Einstein College of Medicine of Yeshiva University, New York, New York
Search for more papers by this authorMenno F. Kielman
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorCorresponding Author
Riccardo Fodde
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The NetherlandsSearch for more papers by this authorRon Smits
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
R. Smits, N. Hofland, and W. Edelmann contributed equally to the work presented in the manuscript.
Search for more papers by this authorNandy Hofland
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
R. Smits, N. Hofland, and W. Edelmann contributed equally to the work presented in the manuscript.
Search for more papers by this authorWinfried Edelmann
Department of Cell Biology, Albert Einstein College of Medicine of Yeshiva University, New York, New York
R. Smits, N. Hofland, and W. Edelmann contributed equally to the work presented in the manuscript.
Search for more papers by this authorMarjan Geugien
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorShantie Jagmohan-Changur
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorCristina Albuquerque
Laboratório de Biologia Molecular, CIPM, Lisbon, Portugal
Search for more papers by this authorCor Breukel
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorRaju Kucherlapati
Department of Molecular Genetics, Albert Einstein College of Medicine of Yeshiva University, New York, New York
Search for more papers by this authorMenno F. Kielman
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Search for more papers by this authorCorresponding Author
Riccardo Fodde
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The NetherlandsSearch for more papers by this authorAbstract
The APC gene, originally identified as the gene for familial adenomatous polyposis (FAP), is now considered as the true “gatekeeper” of colonic epithelial proliferation. Its main tumor suppressing activity seems to reside in the capacity to properly regulate intracellular β-catenin signaling. Most somatic APC mutations are detected between codons 1286 and 1513, the mutation cluster region (MCR). This clustering can be explained either by the presence of mutation-prone sequences within the MCR, or by the selective advantage provided by the resulting truncated polypeptides. Here, a Msh2-deficient mouse model (Msh2Δ7N ) was generated and bred with Apc1638N and ApcMin that allowed the comparison of the somatic mutation spectra along the Apc gene in the different allelic combinations. Mutations identified in Msh2Δ7N/Δ7N tumors are predominantly dinucleotide deletions at simple sequence repeats leading to truncated Apc polypeptides that partially retain the 20 a.a. β-catenin downregulating motifs. In contrast, the somatic mutations identified in the wild type Apc allele of Msh2Δ7N/Δ7N /Apc+/1638N and Msh2Δ7N/Δ7N /Apc+/Min tumors are clustered more to the 5′ end, thereby completely inactivating the β-catenin downregulating activity of APC. These results indicate that somatic Apc mutations are selected during intestinal tumorigenesis and that inactivation of the β-catenin downregulating function of APC is likely to represent the main selective factor. © 2000 Wiley-Liss, Inc.
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