Matrix metalloproteinases (MMPs) are essential for proper extracellular matrix remodeling. We previously found that a membrane-anchored glycoprotein, RECK, negatively regulates MMP-9 and inhibits tumor invasion and metastasis. Here we show that RECK regulates two other MMPs, MMP-2 and MT1-MMP, known to be involved in cancer progression, that mice lacking a functional RECK gene die around E10.5 with defects in collagen fibrils, the basal lamina, and vascular development, and that this phenotype is partially suppressed by MMP-2 null mutation. Also, vascular sprouting is dramatically suppressed in tumors derived from RECK-expressing fibrosarcoma cells grown in nude mice. These results support a role for RECK in the regulation of MMP-2 in vivo and implicate RECK downregulation in tumor angiogenesis.

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Transforming growth factor , (TGF-,B) is a potent inhibitor of epithelial cell growth. Cyclins E and A in association with Cdk2 have been shown to play a role in the GI-to-S phase transition in mammalian cells. We have studied the effects of TGF-p-mediated growth arrest on GJ/S cyclins E and A. Inhibition of cyclin A-associated kinase by TGF-j is primarily due to a decrease in cyclin A mRNA and protein. By contrast, while TGF-0 inhibits accumulation of cyclin E mRNA, the reduction in cyclin E protein is minimal. Instead, we find that the activation of cyclin E-associated kinase that normally accompanies the Gl-to-S phase transition is inhibited. A novel inhibitor of cyclin-Cdk complexes was detected in TGF-j8-treated cell lysates. Inhibition is mediated by a heat-stable protein that targets both Cdk2 and Cdc2 kinases. In Go-arrested cells, a similar inhibitor of Cdk2 kinase was detected. These data suggest the existence of an inhibitor of cyclin-dependent kinases induced under different conditions to mediate antiproliferative responses.Control of the eukaryotic cell cycle occurs at key points in G, and at the G2-to-M phase transition (41,80,85,121,122). These transitions are governed by multimeric protein complexes with serine/threonine kinase activity, whose catalytic subunits, proteins of 33 to 34 kDa, are regulated by phosphorylation and by periodic association with positive effector proteins, known as cyclins. Current understanding of cell cycle control derives largely from studies of yeast cells. The Cdc28 kinase in the budding yeast Saccharomyces cerevisiae and its homolog in the fission yeast Schizosaccharomycespombe, Cdc2, appear to regulate both the Gl-to-S and G2-to-M phase transitions (5,81,88,93,95). In S. cerevisiae, association of p34Cdc28 with Gl cyclins, or Clns, is necessary for entry to S phase (12,38,77,98,115), while association with the mitotic or B-type cyclins, the Clbs, promotes entry into mitosis (30, 108).The first human homolog of p34Cdc2/Cdc28 to be identified, Cdc2Hs, could complement p34 deficiency in both S. cerevisiae and S. pombe (16, 61). However, its action appears to be restricted to the G2-to-M phase transition in humans (15,89,97,110).A number of Cdc2-related or cyclin-dependent kinases (Cdks) have subsequently been identified (23,51,61,74,78,86,102,112). These kinases combine with different cyclins to govern different cell cycle transitions. One of these, Cdk2, appears to regulate Gl-and S-phase functions in human cells (62,102,113). The action of Cdk2 in complex with cyclin A is essential for progression through S phase and may play a role in the regulation of DNA synthesis (25,32,33,83,90,123).Several candidate G, cyclins, designated C, D, and E, were identified when human and Drosophila cDNA libraries were screened for sequences that could complement deletion of the S. cerevisiae Cln genes (51,63,65,117). A cyclin D cDNA was

Gap junctions are unique intercellular channels that connect the cytoplasm of adjacent cells. They are the only channels that mediate the direct cytoplasmic exchange of small hydrophilic molecules between cells--a process called gap junctional communication. Formed by a family of integral membrane proteins called connexins, gap junctions are dynamic multifunctional complexes that are essential for healthy vertebrate development and physiology. Defects in connexin proteins, and, therefore, in gap junctional communication, are associated with a large variety of pathologies in humans and experimental animals. Thus, knowledge of the molecules that pass through gap junction channels is extremely important. However, aside from some notable cases, the repertoire of biologically important transjunctional molecules remains relatively unexplored. Indeed, the study of the intercellular transfer of endogenous molecules presents formidable challenges. Here we review developments in identifying biologically relevant molecules that pass between cells through gap junction channels.

Multi-walled carbon nanotubes have a fibrous structure similar to asbestos and induce mesothelioma when injected into the peritoneal cavity. In the present study, we investigated whether carbon nanotubes administered into the lung through the trachea induce mesothelial lesions. Male F344 rats were treated with 0.5 mL of 500 lg/mL suspensions of multi-walled carbon nanotubes or crocidolite five times over a 9-day period by intrapulmonary spraying. Pleural cavity lavage fluid, lung and chest wall were then collected. Multi-walled carbon nanotubes and crocidolite were found mainly in alveolar macrophages and mediastinal lymph nodes. Importantly, the fibers were also found in the cell pellets of the pleural cavity lavage, mostly in macrophages. Both multi-walled carbon nanotube and crocidolite treatment induced hyperplastic proliferative lesions of the visceral mesothelium, with their proliferating cell nuclear antigen indices approximately 10-fold that of the vehicle control. The hyperplastic lesions were associated with inflammatory cell infiltration and inflammationinduced fibrotic lesions of the pleural tissues. The fibers were not found in the mesothelial proliferative lesions themselves. In the pleural cavity, abundant inflammatory cell infiltration, mainly composed of macrophages, was observed. Conditioned cell culture media of macrophages treated with multi-walled carbon nanotubes and crocidolite and the supernatants of pleural cavity lavage fluid from the dosed rats increased mesothelial cell proliferation in vitro, suggesting that mesothelial proliferative lesions were induced by inflammatory events in the lung and pleural cavity and likely mediated by macrophages. In conclusion, intrapulmonary administration of multi-walled carbon nanotubes, like asbestos, induced mesothelial proliferation potentially associated with mesothelioma development. (Cancer Sci 2012; 103: 2045-2050 M ulti-walled carbon nanotubes (MWCNT) are structurally composed of cylinders rolled up from several layers of graphite sheets. They are several to tens of nanometers in diameter and several to tens of micrometers in length. This high length to diameter aspect ratio, a characteristic shared with asbestos fibers, has led to concern that exposure to MWCNT might cause asbestos-like lung diseases, such as lung fibrosis, lung cancer, pleural plaque and malignant mesothelioma.(1-6) Pleural plaque and malignant mesothelioma are characteristic lesions in asbestos-exposed humans. Although fiber dimensions, biopersistence, oxidative stress and inflammation have all been implicated, (7)(8)(9)(10)(11)(12) the exact mechanisms of pleural pathogenesis are unclear. According to a pathogenesis paradigm suggested by Donaldson et al.,asbestos fibers penetrate into the pleural cavity from the alveoli and deposit in the pleural tissue. Unlike spherical particles, fibrous materials such as asbestos are not cleared effectively from the pleural cavity, resulting in deposition of the fibers in the parietal pleura. This deposition, in turn, causes frustrated ...