Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.
Hirota S. Isozaki K. Moriyama Y. Hashimoto K. Nishida T. Ishiguro S. Kawano K. Hanada M. Kurata A. Takeda M. Muhammad Tunio G. Matsuzawa Y. Kanakura Y. Shinomura Y. Kitamura Y.
Department of Pathology, Osaka University Medical School, Yamada-oka 2-2, Suita 565, Japan.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.
Aspirin-like molecules that covalently inactivate cyclooxygenase-2.
Kalgutkar AS. Crews BC. Rowlinson SW. Garner C. Seibert K. Marnett LJ.
A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Many of aspirin's therapeutic effects arise from its acetylation of cyclooxygenase-2 (COX-2), whereas its antithrombotic and ulcerogenic effects result from its acetylation of COX-1. Here, aspirin-like molecules were designed that preferentially acetylate and irreversibly inactivate COX-2. The most potent of these compounds was o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS). Relative to aspirin, APHS was 60 times as reactive against COX-2 and 100 times as selective for its inhibition; it also inhibited COX-2 in cultured macrophages and colon cancer cells and in the rat air pouch in vivo. Such compounds may lead to the development of aspirin-like drugs for the treatment or prevention of immunological and proliferative diseases without gastrointestinal or hematologic side effects.
Mutations in the SMAD4/DPC4 gene in juvenile polyposis.
Howe JR. Roth S. Ringold JC. Summers RW. Jarvinen HJ. Sistonen P. Tomlinson IP. Houlston RS. Bevan S. Mitros FA. Stone EM. Aaltonen LA.
Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242, USA. firstname.lastname@example.org
Familial juvenile polyposis is an autosomal dominant disease characterized by a predisposition to hamartomatous polyps and gastrointestinal cancer. Here it is shown that a subset of juvenile polyposis families carry germ line mutations in the gene SMAD4 (also known as DPC4), located on chromosome 18q21.1, that encodes a critical cytoplasmic mediator in the transforming growth factor-beta signaling pathway. The mutant SMAD4 proteins are predicted to be truncated at the carboxyl-terminus and lack sequences required for normal function. These results confirm an important role for SMAD4 in the development of gastrointestinal tumors.