The modifier of Min 2 (Mom2) locus: embryonic lethality of a mutation in the Atp5a1 gene suggests a novel mechanism of polyp suppression.

Authors

Amy A Baran, Kimmel Cancer Center, Thomas Jefferson University, Jefferson Medical CollegeFollow
Karen A Silverman, Kimmel Cancer Center, Thomas Jefferson University, Jefferson Medical College; Children's Hospital of PhiladelphiaFollow
Joseph Zeskand, Kimmel Cancer Center, Thomas Jefferson University, Jefferson Medical College; Alexion PharmaceuticalsFollow
Revati Koratkar, Kimmel Cancer Center, Thomas Jefferson University, Jefferson Medical College
Ashley Palmer, Kimmel Cancer Center, Thomas Jefferson University, Jefferson Medical College; Hematology Department, Brigham and Women's Hospital
Kristen McCullen, Department of Obstetrics and Gynecology, Thomas Jefferson University, Jefferson Medical CollegeFollow
Walter J Curran, Kimmel Cancer Center, Thomas Jefferson University, Jefferson Medical CollegeFollow
Tina Bocker Edmonston, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Jefferson Medical CollegeFollow
Linda D Siracusa, Kimmel Cancer Center, Thomas Jefferson University, Jefferson Medical CollegeFollow
Arthur M Buchberg, Kimmel Cancer Center, Thomas Jefferson University, Jefferson Medical CollegeFollow

Document Type

Article

Publication Date

5-1-2007

Comments

This article has been peer reviewed and is published in Genome Research 2007, 17: 566-576. The published version is available at DOI: 10.1101/gr.6089707. ©Cold Spring Harbor Laboratory Press

Abstract

Inactivation of the APC gene is considered the initiating event in human colorectal cancer. Modifier genes that influence the penetrance of mutations in tumor-suppressor genes hold great potential for preventing the development of cancer. The mechanism by which modifier genes alter adenoma incidence can be readily studied in mice that inherit mutations in the Apc gene. We identified a new modifier locus of ApcMin-induced intestinal tumorigenesis called Modifier of Min 2 (Mom2). The polyp-resistant Mom2R phenotype resulted from a spontaneous mutation and linkage analysis localized Mom2 to distal chromosome 18. To obtain recombinant chromosomes for use in refining the Mom2 interval, we generated congenic DBA.B6 ApcMin/+, Mom2R/+ mice. An intercross revealed that Mom2R encodes a recessive embryonic lethal mutation. We devised an exclusion strategy for mapping the Mom2 locus using embryonic lethality as a method of selection. Expression and sequence analyses of candidate genes identified a duplication of four nucleotides within exon 3 of the alpha subunit of the ATP synthase (Atp5a1) gene. Tumor analyses revealed a novel mechanism of polyp suppression by Mom2R in Min mice. Furthermore, we show that more adenomas progress to carcinomas in Min mice that carry the Mom2R mutation. The absence of loss of heterozygosity (LOH) at the Apc locus, combined with the tendency of adenomas to progress to carcinomas, indicates that the sequence of events leading to tumors in ApcMin/+ Mom2R/+ mice is consistent with the features of human tumor initiation and progression.

Recommended Citation

Baran, Amy A; Silverman, Karen A; Zeskand, Joseph; Koratkar, Revati; Palmer, Ashley; McCullen, Kristen; Curran, Walter J; Edmonston, Tina Bocker; Siracusa, Linda D; and Buchberg, Arthur M, "The modifier of Min 2 (Mom2) locus: embryonic lethality of a mutation in the Atp5a1 gene suggests a novel mechanism of polyp suppression." (2007). Kimmel Cancer Center Faculty Papers. Paper 14.
https://jdc.jefferson.edu/kimmelccfp/14

PubMed ID

17387143