The adhesion receptor SHPS-1 activates the proteintyrosine-phosphatase SHP-2 and thereby promotes integrin-mediated reorganization of the cytoskeleton.

Physical exercise ameliorates metabolic disorders such as type 2 diabetes mellitus and obesity, but the molecular basis of these effects remains elusive. In the present study, we found that exercise up-regulates heparin-binding epidermal growth factor-like growth factor (HB-EGF) in skeletal muscle. To address the metabolic consequences of such gain of HB-EGF function, we generated mice that overexpress this protein specifically in muscle. The transgenic animals exhibited a higher respiratory quotient than did wild-type mice during indirect calorimetry, indicative of their selective use of carbohydrate rather than fat as an energy substrate. They also showed substantial increases in glucose tolerance, insulin sensitivity, and glucose uptake by skeletal muscle. These changes were accompanied by increased kinase activity of Akt in skeletal muscle and consequent inhibition of Forkhead box O1-dependent expression of the pyruvate dehydrogenase kinase 4 gene. Furthermore, mice with a high level of transgene expression were largely protected from obesity, hepatic steatosis, and insulin resistance, even when maintained on a high-fat diet. Our results suggest that HB-EGF produced by contracting muscle acts as an insulin sensitizer that facilitates peripheral glucose disposal.

The retinoblastoma gene product (RB protein) plays a key role in the progression of the cell cycle from G1 to S phase in normal and neoplastic cells. The activity of RB is regulated by phosphorylation and dephosphorylation with cell-cycle-dependent protein kinases. We investigated the effect of the protein kinase inhibitors, staurosporine and 7-hydroxy-staurosporine (UCN-01), on RB protein expression of N417 small cell lung cancer cells (absent RB), H209 small cell lung cancer cells (mutant RB), and Ma-31 non-small cell lung cancer cells (wild-type RB), using immunologic blotting. Staurosporine and UCN-01 each suppressed the growth of N417, H209 and Ma-31 cells in a dose-dependent manner in MTT assay. IC50 values of staurosporine for N417, H209 and Ma-31 cells were 54, 29 and 602 nM, respectively. IC50 values of UCN-01 for N417, H209 and Ma-31 cells were 737,181 and 2,197 nM, respectively. Exposure to staurosporine and UCN-01 for 72 h each suppressed the level of expression and altered the ratio of phosphorylated/dephosphorylated RB protein (ppRB/pRB) of Ma-31 cells. Conversely, these agents increased the expression level of RB protein at concentrations less than IC50, and did not change phosphorylation status of mutant RB protein of H209 cells at the concentrations studied. A time course study demonstrated that exposure to the IC50 concentration of staurosporine for 48–72 h increased the ratio of ppRB/ pRB of Ma-31 cells, while exposure to the IC50 concentration of UCN-01 decreased that ratio. UCN-01 increased % cells in G2+M phase and decreased % cells in S phase, while staurosporine increased % cells in G1 phase and decreased % cells in G2+M phase. UCN-01 did not induce apoptosis (DNA content < 2N) of Ma-31 cells, but staurosporine induced it. These findings suggest that the differing effects of staurosporine and UCN-01 on RB protein expression and cell cycle phases of lung cancer cells may explain their differing in vivo antitumor effect of staurosporine and UCN-01 despite their similar chemical structures.

Background. It has been suggested that the genetic abnormality responsible for von Recklinghausen neurofibromatosis (NF1) increases a patient's risk of various kinds of malignancies. The incidence of small cell lung carcinoma (SCLC) as a complication of NF1, however, is rare. To clarify the relationship between NF1 and SCLC, possible loss of heterozygosity of chromosome 17 in a patient with SCLC combined with NF1 was analyzed. Methods. Possible loss of heterozygosity for chromosome 17 was analyzed by a molecular genetic approach using several chromosome 17‐specific polymorphic DNA markers. Results. In both primary tumor and metastatic tumors of SCLC, loss of heterozygosity was detected on chromosome arm 17p, but not on 17q. Loss of heterozygosity, however, was detected on neither 17p nor 17q in neurofibromas and normal tissue. Conclusions. The formation of SCLC may result from several genetic alterations, including inactivation of tumor‐suppressor gene on chromosome 17p, most likely P53, although it still is unknown whether or not a mutation of the NF1 gene on 17q was involved in the development of SCLC in this patient.

Objective. The aim of this study was to investigate changes in brain and muscle glucose metabolism that are not yet known, using positron emission tomography with [18F]fluorodeoxyglucose ([18F]FDG PET). Methods. Twenty-one male volunteers were recruited for the present study. [18F]FDG PET scanning was performed twice on each subject: once after the spinal manipulation therapy (SMT) intervention (treatment condition) and once after resting (control condition). We performed the SMT intervention using an adjustment device. Glucose metabolism of the brain and skeletal muscles was measured and compared between the two conditions. In addition, we measured salivary amylase level as an index of autonomic nervous system (ANS) activity, as well as muscle tension and subjective pain intensity in each subject. Results. Changes in brain activity after SMT included activation of the dorsal anterior cingulate cortex, cerebellar vermis, and somatosensory association cortex and deactivation of the prefrontal cortex and temporal sites. Glucose uptake in skeletal muscles showed a trend toward decreased metabolism after SMT, although the difference was not significant. Other measurements indicated relaxation of cervical muscle tension, decrease in salivary amylase level (suppression of sympathetic nerve activity), and pain relief after SMT. Conclusion. Brain processing after SMT may lead to physiological relaxation via a decrease in sympathetic nerve activity.