The six-ankyrin repeat containing Asb genes may drive normal and adenomatous compartment size expansion in the distal intestine

Dysregulation of compartment size is maybe the most fundamental biological issue in cancer. Important clues as to novel therapeutical avenues for dealing with this disease may thus be obtained from the regulation of compartment size in untranstormed cells. Previously we reported the extraction of d-asb11 from a screen in zebrafish to identify gene products essential for maintaining proliferation progenitors during embryogenesis and established that it is a major determinant regulating the size of the central nervous system; knock down of the gene leading to a small brain, whereas its forced expression led to a massive expansion of the zebrafish central nervous system and brain hypertrophy. Here we compare zebrafish d-asb11 to the human genome and identify a subfamily within the group of Asb genes consisting apart from human ASB11 of ASB5, ASB9, and ASB13 which are highly structurally related, very homologous and among the most conserved genes in the chordate phylum. Analysis of forced expression of d-asb11 in zebrafish suggests the gene has the capacity to expand endodermal domains and thus we explore the expression of Asb5, Asb9, Asb11 and Asb13 in the untransformed mammalian gastrointestinal system and possible deregulation in gastrointestinal cancer. We observe low but distinct expression of various Asbs in the different elements of the gastrointestinal tract suggesting Asb-coding within the endoderm may exist. Asb9 appears most important, especially in the distal tract and its expression is highly upregulated in colonic cancer. The study indicates that Asb11-like members of the Asb family of proteins might be implicated in compartment expansion in the gastrointestinal tract and prompt further investigations as to their roles in cancer in derivatives of the endodermal lineage.