The modifier ofMin2 (Mom2) locus: Embryonic lethality of a mutation in theAtp5a1gene suggests a novel mechanism of polyp suppression

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. R 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 ␣ subunit of the ATP synthase (Atp5a1) gene. Tumor analyses revealed a novel mechanism of polyp suppression by Mom2 R in Min mice. Furthermore, we show that more adenomas progress to carcinomas in Min mice that carry the Mom2 R 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 Apc Min/+ Mom2 R/+ mice is consistent with the features of human tumor initiation and progression.[Supplemental material is available online at www.genome.org.]Colorectal cancer is one of the leading causes of cancer deaths in the United States (www.cancer.org). The dysregulation of normal colonic epithelium leads to the formation of adenomas, which are considered a prerequisite to progression to carcinoma (Fodde et al. 2003). This multistep process involves interactions between the genome and the gut environment, leading to mutations and epigenetic changes in oncogenes and/or tumor suppressor genes (Kinzler and Vogelstein 1996;Ilyas et al. 1999;Gregorieff and Clevers 2005). However, the variation in penetrance of hereditary forms of cancer has emphasized the impact of tumormodifier genes that can influence individual susceptibility to cancer by either enhancing or suppressing the initiation, growth, and/or progression of tumor cells. Due to environmental and genetic heterogeneity in the human population, it has been difficult to identify tumor modifier loci in humans. Therefore, complex trait analysis in experimental mouse crosses is a powerful approach to genetically dissect multigenic diseases (Moore and Nagle 2000;Threadgill et al. 2002;Siracusa et al. 2004).The mapping, identification, and characterization of genes influencing tumor susceptibility has been facilitated by the use of mammalian models (Mao and Balmain 2003). Inbred strains of mice that differ in their susceptibility to various types of solid tumors and leukemias have been instrumental in uncovering loci that affect tumor risk (Dragani 2003;Mao and Balmain 2003). Tumor susceptibility genes may act cell autonomously within the tumor lineage, or may act in a non-cell autonomous fashion within the microenvironment leading to tumor formation (Demant 2003). Genomic differences among inbred strains of mice are being exploited to limit the regions containing the causative allelic variants and ul...

Expression of Eleven Egg Performance-associated Genes in the Ovary of Zi Geese <i>Anser anser domestica</i>

“…The ATP5A1 gene is essential for aerobic respiration (Schnaufer et al, 2005), and its absence results in cell death (Baran et al, 2007). Therefore, the expression level of ATP5A1 was higher in the ovaries of laying geese is the result of high metabolic activity in the ovaries because of a great quantity of ATP generated by aerobic respiration.…”

The Pleiotropic Phenotype of Apc Mutations in the Mouse: Allele Specificity and Effects of the Genetic Background

“…The difference in intestinal tumor multiplicity between two Apc alleles, the nonsense allele Min and the insertion allele 1638N, can be explained either by a dominant-negative activity of the Min allele or, as for Mom2 (Baran et al 2007), by a position effect in which the 1638N insertion affects expression of a neighboring cell-vital gene (Haigis et al 2004). In contrast to the vast preponderance of loss-of-heterozygosity (LOH) seen in Min tumors on the B6 background (Luongo et al 1994;Haigis et al 2002;Haigis and Dove 2003), the majority of tumors in B6 Apc 1638N/+ mice do not show LOH.…”

Genetic control of susceptibility to carcinogen-induced colorectal cancer in mice: TheCcs3andCcs5loci regulate different aspects of tumorigenesis

“…1p35-36) showing conserved synteny with mouse Mom1 and Mom4 have been associated with familial and sporadic cases of CRC. [37][38][39] The Mom1 and Mom2 modifier effects have been linked to Pla2g2a and Atp5a1, affecting prostaglandin biosynthesis 40 and hypoxia-induced tumor progression, 41 respectively. Together, these studies have demonstrated the usefulness of genetic analysis in mouse models to identify genes relevant to CRC pathogenesis in humans.…”