Intestinal insulin/IGF1 signalling through FoxO1 regulates epithelial integrity and susceptibility to colon cancer.

Obesity promotes the development of insulin resistance and increases the incidence of colitis-associated cancer (CAC), but whether a blunted insulin action specifically in intestinal epithelial cells (IECs) affects CAC is unknown. Here, we show that obesity impairs insulin sensitivity in IECs and that mice with IEC-specific inactivation of the insulin and IGF1 receptors exhibit enhanced CAC development as a consequence of impaired restoration of gut barrier function. Blunted insulin signalling retains the transcription factor FOXO1 in the nucleus to inhibit expression of Dsc3, thereby impairing desmosome formation and epithelial integrity. Both IEC-specific nuclear FoxO1ADA expression and IEC-specific Dsc3 inactivation recapitulate the impaired intestinal integrity and increased CAC burden. Spontaneous colonic tumour formation and compromised intestinal integrity are also observed upon IEC-specific coexpression of FoxO1ADA and a stable Myc variant, thus suggesting a molecular mechanism through which impaired insulin action and nuclear FOXO1 in IECs promotes CAC.

Structure and chromosomal assignment of a gene encoding the major protein of rat sperm outer dense fibres.

Outer dense fibres are located on the outside of the axoneme in the midpiece and principal piece of the mammalian sperm tail and may help to maintain the passive elastic structures and elastic recoil of the sperm tail. Here we describe the isolation and genomic organization of a rat gene encoding a cysteine-proline-rich outer dense fibre protein. The cDNA sequence of rts 5/1 and its expression pattern have already been published [Burfeind, P. & Hoyer-Fender, S. (1991) Dev. Biol. 148, 195-204]. There exist two different genes in the rat genome, rts 5/1 major and rts 5/1 minor. Rts 5/1 major consists of two exons interrupted by one intron of about 3.8 kb. Exon 1 and rts 5/1 minor contains a deletion of 120 bp, without destroying the open reading frame, which is flanked by short direct repeats, 15 bp in length. The first two nucleotides of the intronic sequence were identified as GA and, therefore, do not agree with the donor consensus sequence. From the analysis of mouse x rat cell hybrids, the rts 5/1 major gene has been assigned to chromosome 7. By immunoblotting and immunocytochemistry, it was demonstrated that the isolated gene encodes a major protein of rat sperm outer dense fibres.