Abstract
Virulent type I strains of Helicobacter pylori express the protein CagA and inject it into gastric epithelial cells after attaching to the cells. Patients with CagA+ H. pylori have increased frequency of gastric carcinoma and lymphoma. However, the molecular basis for oncogenesis is unknown. Investigators have shown that CagA alone is sufficient to induce a growth-factor-like phenotypic response in gastric epithelial cells. CagA undergoes tyrosine phosphorylation, localizes to the plasma membrane, and binds SHP-2, a cytoplasmic tyrosine kinase with two SH2 domains. This binding activates SHP-2 by lifting its autoinhibition. SHP-2 is involved in signal transduction by connecting receptor tyrosine kinases and ras, leading to activation of the ras/raf/MAP kinase signaling pathway, phosphorylation of regulatory proteins and transcription factors, and ultimately cell proliferation. SH2 is also involved in the spreading, migration, and adhesion of cells. The pathogenesis of CagA associated gastric carcinoma may involve deregulation of SHP-2. This is the first demonstration of a potential molecular mechanism for H. pylori-associated gastric carcinoma.
Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M, Hatakeyama M: SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295: 683–686, 2002
Contributed by Dr. N. L. Stedman, University of Georgia, Athens, GA
To determine the effect of strain background on the repair response to acute bronchiolar injury, investigators compared the effect of naphthalene in Swiss Webster, C57BL/6, 129/TerSv, and 129/SvEv mice. To evaluate ciliated cell squamation, proliferation, and epithelial differentiation, the following parameters were determined at 1, 2, 4, 7, and 14 days after intraperitoneal administration of naphthalene: ciliated cell surface area, BrdU incorporation, and number of ciliated cells per unit of surface area. The extent of Clara cell injury was the same for all strains of mice; however, the time of onset, speed, and pattern of repair differed markedly among the strains. Genetically engineered mice are often produced on a complex C57BL/6 × 129 background. On the basis of their studies, these investigators concluded that it is essential to compare genetically engineered and control mice of identical strain background in all studies using such mice.
Lawson GW, Van Winkle LS, Toskala E, Senior RM, Parks WC, Plopper CG: Mouse strain modulates the role of the ciliated cell in acute tracheobronchial airway injury-distal airways. Am J Pathol 160: 315–327, 2002
Germline defects in the BRCA2 gene in humans dramatically enhance the risk for a variety of tumors, including carcinomas of the breast, ovary, pancreas, colon, prostate, stomach, larynx, and thyroid. To date, no good animal model of the human condition has been available because Brca2 knockout embryos rarely survive until birth and the few that survive are infertile. American scientists recently produced a Brca2 knockout mouse that suffers only limited perinatal mortality, is fertile, and shows more than a twofold increase in the incidence of spontaneous tumors (carcinomas, sarcomas, and lymphomas). The Brca2 gene in these mice was inactivated by removal of exon 27; this exon encodes a region of the protein that interacts with the Rad51 protein, contains a nuclear localization signal, and is essential for preventing genomic instability after DNA damage. These mice will be valuable for studying the tumor suppressor activity of Brca2.
McAllister KA, Bennett LM, Houle CD, Ward T, Malphurs J, Collins NK, Cachafeiro C, Haseman J, Goulding EH, Bunch D, Eddy EM, Davios BJ, Wiseman RW: Cancer susceptibility of mice with a homozygous deletion in the COOH-terminal domain of the Brca2 gene. Cancer Res 62: 990–994, 2002
To treat the progressive loss of dopamine neurons responsible for Parkinson's disease in humans, fetal dopaminergic cells can be implanted into the brain. However, it is often difficult to obtain fetal material suitable for transplantation. A group of international scientists has now demonstrated that embryonal stem (ES) cells may also be employed. Lesions were introduced into the median forebrain bundle of rats, then low numbers of mouse ES cells were introduced into the striatum; cyclosporine A immunosuppression prevented graft rejection. The ES cells developed into cells resembling dopaminergic neurons and appeared to restore neurologic functions impaired by the previously introduced brain lesions. It appeared that differentiation of ES cells into neurons was fostered by injection of low numbers of individualized ES cells and the striatal site of transplantation. This technique offers an attractive alternative to the use of fetal tissue in treating Parkinson's disease.
Björklund LM, Sánchez-Pernaute R, Chung S, Andersson T, Chen IYC, McNaught KSP, Brownell AL, Jenkins BG, Wahlestedt C, Kim KS, Isacson O: Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 99: 2344–2349, 2002
In large-scale mutagenesis studies now underway in mice, many cerebellar defects are readily identified by virtue of the ataxia they cause. To investigate cerebellar patterning in such mice, Canadian scientists developed a high-throughput technique of staining for zebrin II by whole-mount immunohistochemistry. Isolated perfusion-fixed or immersion-fixed cerebellums were postfixed in Dent's fixative, incubated in Dent's bleach, dehydrated in methanol, subjected to freeze-thawing in methanol, rehydrated, treated with proteinase K, stained using standard immunohistochemical reagents, and cleared. Using this technique, the investigators detected a variety of antigens in all layers of the cerebellum, although more peripheral regions were more readily accessible to reagents than more deeply buried areas. This technique permits pattern visualization in large anatomic structures without the need for time-consuming sectioning and three-dimensional reconstruction.
Sillitoe RV, Hawkes R: Whole-mount immunohistochemistry: a high-throughput screen for patterning defects in the mouse cerebellum. J Histochem Cytochem 50: 235–244, 2002
The role of type 2 porcine circovirus (PCV2) in postweaning multisystemic wasting syndrome (PMWS) in pigs has been controversial. To investigate this issue, American researchers constructed an infectious molecular clone of PCV2 and used this clone to infect pigs by directly injecting cloned DNA into the livers or superficial iliac lymph nodes. Injected pigs seroconverted and developed gross lesions of multifocal lung consolidation and lymphadenopathy. Microscopic lesions included multifocal lymphoplasmacytic inflammation in many tissues, especially lung, liver, brain, heart, and kidney, and lymphoid depletion and granulomatous inflammation in lymphoid organs (excluding the thymus). Thus, infection with PCV2 reproduced the microscopic lesions of PMWS, but characteristic clinical disease manifestations were not observed, suggesting that additional factors contribute to full expression of the disease syndrome.
Fenaux M, Halbur PG, Haqshenas G, Royer R, Thomas P, Nawagitgul P, Gill M, Toth TE, Meng XJ: Cloned genomic DNA of type 2 porcine circovirus is infectious when injected directly into the liver and lymph nodes of pigs: characterization of clinical disease, virus distribution, and pathologic lesions. J Virol 76: 541–551, 2002