Brian G. Fuller

Gastric carcinoma may occur sporadically or in association with hereditary diseases, such as Peutz-Jehgers syndrome (PJS). The PJS gene (named STK11 or LKB1) was mapped to 19p13.3 and recently cloned. Germ-line mutations of the gene have been detected in familial PJS patients and are predicted to predispose STK11 carriers to the development of a wide range of gastrointestinal and other neoplasms. To elucidate the etiological role of the STK11 gene in sporadic gastric carcinoma tumorigenesis, we analyzed 28 gastric carcinomas (22 of intestinal type and 6 of diffuse type) for STK11 gene mutations. STK11 gene mutations were detected in 3 of 28 gastric carcinomas but were not seen in the corresponding germ-line DNA sequence. In one tumor, a missense mutation, C-to-T transition, was detected at codon 324 resulting in proline to leucine substitution; in the other two, silent mutations were detected at codons 106 and 350, respectively. While these results suggest that somatic STK11 mutations are not common in sporadic gastric carcinomas, they may occur in a subset of these tumors.

Gradients are used in a number of biological systems to transmit spatial information over a range of distances. The best studied are morphogen gradients where information is transmitted over many cell lengths. Smaller mitotic gradients reflect the need to organize several distinct events along the length of the mitotic spindle. The intracellular gradients that characterize mitosis are emerging as important regulatory paradigms. Intracellular gradients utilize intrinsic auto-regulatory feedback loops and diffusion to establish stable regions of activity within the mitotic cytosol. We review three recently described intracellular mitotic gradients. The Ran GTP gradient with its elaborate cascade of nuclear transport receptors and cargoes is the best characterized, yet the dynamics underlying the robust gradient of Ran-GTP have received little attention. Gradients of phosphorylation have been observed on Aurora B kinase substrates both before and after anaphase onset. In both instances the phosphorylation gradient appears to result from a soluble gradient of Aurora B kinase activity. Regulatory properties that support gradient formation are highlighted. Intracellular activity gradients that regulate localized mitotic events bare several hallmarks of self-organizing biologic systems that designate spatial information during pattern formation. Intracellular pattern formation represents a new paradigm in mitotic regulation.