CD44 Enhances Neuregulin Signaling by Schwann Cells

Sherman L, Rizvi TA, Karyala S, Ratner N. J Cell Biol 2000; 150:1071-1083 (Department of Cell Biology, Neurobiology and Anatomy)

This study demonstrates that CD44, a transmembrane glycoprotein, can mediate the activities of two oncogenes that normally mediate Schwann cell differentiation, proliferation and survival. These results have important consequences for understanding peripheral nerve development, tumorigenesis, and response to injury.

Mitotic recombination produces the majority of recessive somatic variants in heterozygous mice.

Shao C, Deng L, Henegariu O, Liang L, Raikwar N, Sahota A, Stambrook PJ., Tischfield JA. Proc Natl Acad Sci USA 1999; 96:9230-9235 (Department of Cell Biology, Neurobiology and Anatomy).

This report deals with genomic instability and mutagenesis in vivo. One contributing factor to chromosome instability and non-disjunction is an activating mutation in the RAS oncogene. The endogenous Aprt gene is used as a reporter of mutagenic activity for in vivo analysis of mutation and chromosome instability.

MAPK mediates RAS-induced chromosome instability.

Saavedra HI, Fukasawa K, Conn CW, Stambrook PJ. J Biol Chem 1999; 274:38083-38090 (Department of Cell Biology, Neurobiology and Anatomy).

This report addresses the interaction between MAPK and RAS in enhancing genomic instability.

Pneumocysterol [(24Z)-ethylidenelanost-8-en-3beta-ol], a rare sterol detected in the opportunistic pathogen Pneumocystis carinii hominis: structural identity and chemical synthesis.

Kaneshiro ES, Amit Z, Swonger MM, Kreishman GP, Brooks EE, Kreishman M, Jayasimhulu K, Parish EJ, Sun H, Kizito SA, Beach DH. Proc Natl Acad Sci USA 1999; 96:97-102 (Department of Biological Sciences).

Pneumocystis carinii, a fungus that is the most prevalent opportunistic infectious agent in AIDS patients, lacks ergosterol, which is the target of drugs currently used to treat mycotic infections. Instead, the pathogen synthesizes a number of distinct , 24-alkylsterols, which it can scavenge from the lung alveolus. Thus, the pathogen-specific sterols appear vital for organism survival and proliferation. High concentrations of several 24-alkylsterols were found in P. carinii hominis, suggesting that sterol C-24 methyltransferase activities are extraordinarily high in this organism. Because mammals cannot form 24-alkylsterols, their biosyntheses in P. carinii are attractive targets for the development of chemotherapeutic strategies against this opportunistic infection.

CC chemokine receptor-3 undergoes prolonged ligand-induced internalization

Zimmermann N, Conkright JJ, Rothenberg ME. J Biol Chem 1999; 274:12611-12618 (Department of Pediatrics).

The major eosinophil chemokine receptor is CCR3, a G-protein linked seven transmembrane spanning molecule. In this report, a molecular dissection of the intracellular trafficking of CCR3 following ligand binding is uncovered. The results reveal a distinct mechanism involving receptor endocytosis.

Morphological Transformation Induced by Activation of the MAPK Pathway Requires Suppression of the T-type Ca²⁺ Channel

Strobeck MW, Okuda M, Yamaguchi H, Schwartz A, Fukasawa K. J Biol Chem 1999; 274, 15694-15700 (Department of Cell Biology, Neurobiology & Anatomy).

Activation of the mitogen-activated protein kinase (MAPK) pathway is a converging down stream event of transforming activities of many oncogene products, and commonly found in human cancers. Intracellular calcium is known to regulate cellular morphology. In fibroblasts, Ca²⁺ influx is controlled by two types of Ca²⁺ channels (T- and L-types). The authors report that the T-type current was specifically inhibited in cells expressing oncogenically activated Ras as well as gain-of-function mutant MEK (a direct activator of MAPK), while treatment of ras-transformed cells with a MEK-specific inhibitor restored T-type Ca²⁺ channel activity. Using a T-type Ca²⁺ channel antagonist, they further found that suppression of the T-type Ca²⁺ channel by the activated MAPK pathway is a prerequisite event for the induction and/or maintenance of transformation-associated morphological changes.

Cyclin A is a functional target of retinoblastoma tumor suppressor protein-mediated cell cycle arrest.

Knudsen KE, Fribourg AF, Strobeck MW, Blanchard JM, Knudsen ES. J Biol Chem. 1999; 274:27632-41 (Department of Cell Biology, Neurobiology and Anatomy).

This work demonstrated that signaling down-stream from RB is disrupted by cyclin E and identified cyclin A as a critical down-stream target of RB

DNA fragmentation factor 45-deficient cells are more resistant to apoptosis and exhibit different dying morphology than wild-type control cells.

Zhang J, Wang X, Bove KE, Xu M. J Biol Chem 1999; 274:37450-37454 (Department of Cell Biology, Neurobiology and Anatomy).

This study describes an important new mouse model to study DNA fragmentation factor 45 (DFF45), a key molecule that regulates DNA fragmentation upon activation of apoptosis. Programmed cell death is abnormal in this DNA fragmentation factor 45 knockout mouse. This mouse model will be extremely useful for studying the role of DFF45 in cancer, autoimmune diseases and neurodegenerative diseases.

Activation of human estrogen receptor by the antiestrogen ICI 182,780 and tamoxifen in yeast genetic systems: implications for their mechanism of action.

Dudley MW, Sheeler CQ, Wang H, Khan S. Proc Natl Acad Sci USA, 2000; 97: 3696-3701 (Department of Cell Biology, Neurobiology and Anatomy).

This report demonstrates that the antiestrogenic activity of the compounds tamoxifen and ICI 182,780 does not result from their ability to competitively antagonize estradiol binding to the hormone-binding site, but possibly by their ability to induce estrogen receptor-dependent transcription, which in mammalian system would result in receptor down regulation. Compounds such as tamoxifen act through the hormone-binding site , whereas ICI 182,80 may cause receptor activation through an allosteric binding site.

A critical role for eotaxin in experimental oral antigen-induced eosinophilic gastroenteritis

Hogan SP, Mishra A, Brandt E, Foster PS, Rothenberg ME. Proc Natl Acad Sci USA 2000; 97:6681-6686 (Department of Pediatrics).

The first experimental model for eosinophil associated gastroenteritis is described and employed to dissect critical immunological mechanisms. Eotaxin, an eosinophil chemoattractant, is identified as an essential cytokine involved in gut allergy.

Chromosomal instability in vivo in fibroblasts of p53 knockout mice.

Shao C, Deng L, Henegariu O, Liang L, Raikwar N, Stambrook PJ, Tischfield JA. Proc Natl Acad Sci USA 2000; 97:7405-7410 (Department of Cell Biology, Neurobiology and Anatomy).

The authors report that knockout of the p⁵³ tumor suppressor gene results in chromosomal instability in mouse fibroblasts.

BRG-1 is required for RB-mediated cell cycle arrest.

Strobeck MW, Knudsen KE, Fribourg AF, DeCristofaro MF, Weissman BE, Imbalzano AN, Knudsen ES. Proc Natl Acad Sci USA 2000; 97:7748-53 (Department of Cell Biology, Neurobiology and Anatomy).

This work illustrated that specific tumor cell-types bypass RB-mediated cell cycle inhibition via inactivation of the SWI/SNF chromatin remodeling protein, BRG-1.

Aromatic hydrocarbon receptor interaction with the retinoblastoma Protein potentiates Repression of E2F-Dependent Transcription and Cell Cycle Arrest.

Puga A, Barnes SJ, Dalton TP, Chang C-Y, Knudsen ES, Maier A. J Biol Chem 2000; 275:2943-2950 (Departments of Environmental Health and Cell Biology, Neurobiology and Anatomy).

Polyhalogenated aromatic hydrocarbons, of which 2,3,7,8-tetrachloro-p-dioxin (TCDD) is the prototype compound, are ubiquitous environmental toxicants that elicit many toxic responses, including marked effects on the regulation of cell cycle progression. The action of these compounds is mediated by a receptor, termed Ah receptor (AHR), which is a ligand-activated transcription factor that regulates the expression of a battery of detoxification genes. This work demonstrates that AHR can form complexes in the cell with the retinoblastoma protein (RB) and that these complexes synergize to repress E2F-dependent transcription and to induce cell cycle arrest. These results uncover a function for the AHR in cell cycle regulation and suggest that the AHR may serve as an environmental sensor that signals cell cycle arrest when cells are exposed to certain environmental toxicants.

Single Cell Ras-GTP analysis reveals altered Ras activity in a subpopulation of neurofibroma Schwann cells but not fibroblasts.

Sherman LS, Atit R, Rosenbaum T, Cox AD, Ratner N. J Biol Chem 2000; in press (Department of Cell Biology, Neurobiology and Anatomy).

This paper reports a new technique to see activated, GTP-bound Ras molecules using immunohistochemistry, used here to visualize activated Ras in primary cells in culture lacking the NF1 tumor suppressor protein.

Nucleophosmin/B23 is a target of CDK2-cyclin E in centrosome duplication

Okuda M, Horn HF, Tarapore P, Tokuyama Y, Smulian AG, Chan P-K, Knudsen ES, Hofmann IA, Snyder JD, Bove KE, Fukasawa K. Cell 2000; in press (Department of Cell Biology, Neurobiology & Anatomy).

NPM/B23 possess diverse functions: ribosome assembly, protein chaperoning, and nuclear-cytoplasmic trafficking. This report shows that NPM/B23 binds to the centrosomes, and dissociates from the centrosomes upon phosphorylation by CDK2-cyclin E kinase complexes. The dissociation of NPM/B23 in turn signals to the centrosomes to initiate duplication. Thus, NPM/B23 acts as a licensing factor for the centrosomes to duplicate. This study provides a very first molecular level dissection of the centrosome duplication control.