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Biomedical subjects

G L Gusella

Publications and source records attributed to G L Gusella.

25 records · Page 2Linked to original sources
PubMed1991

Human Harvey-ras is biochemically different from Kirsten- or N-ras.

The biochemical effects of the human H-, N- and K-ras oncogenes were studied. We analysed the induction of c-fos mRNA and protein by the protein kinase C (PKC) activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in exponentially growing NIH3T3 fibroblasts transformed by transfection with ras oncogenes. We found that H-ras has the unique ability to inhibit c-fos induction by TPA. In contrast, normal c-fos expression was induced by TPA in fibroblasts transformed by N- or K-ras or by the ras-unrelated oncogenes dbl and trk. The inhibition of c-fos induction by H-ras was not due to alteration in the binding of TPA to the transformed cells or to the selection of idiosyncratic clones. These results provide clear evidence that H-ras is functionally different from K- or N-ras.

Animals↗
PubMed1990

Transforming growth factor beta downregulates interleukin-1 (IL-1)-induced IL-6 production by human monocytes.

We investigated the effects of transforming growth factor beta (TGF beta) on the induction by interleukin-1 beta (IL-1 beta) of IL-6 in human monocytes. We found that IL-1 beta induced IL-6 messenger RNA expression in elutriated monocytes and IL-6 secretion in the supernatant. TGF beta did not induce IL-6. In contrast, TGF beta added to the culture inhibited, in a dose-dependent manner, the induction of IL-6 by IL-1 at the level of messenger RNA and bioactivity. These results show that IL-1 beta is able to stimulate IL-6 production by monocytes, TGF beta, by inhibiting this effect, may play an important role in regulating the IL-1-mediated components of the inflammatory response.

Blotting, Northern↗
PubMed1990

IL-2 enhances c-fms expression in human monocytes.

We investigated the effects of IL-2 and IFN-gamma on the expression of the proto-oncogene c-fms mRNA, which encodes for the macrophage CSF receptor. Low constitutive expression of c-fms mRNA was detected in fresh human monocytes. Stimulation of monocytes with IL-2 induced a significant increase in c-fms mRNA relative to medium control that was observed as early as 6 h after IL-2 stimulation. Dose-response experiments showed that 100 U/ml of IL-2 were sufficient to enhance the expression of c-fms mRNA. In contrast, IFN-gamma did not modify the levels of c-fms transcript. Immunoprecipitation experiments demonstrated that IL-2 enhanced c-fms glycoprotein levels. Experiments in which monocytes were activated with IFN-gamma or IL-2 followed by macrophage CSF-1 and then tested for tumoricidal activity demonstrated that macrophage CSF-1 sustained the cytotoxic activity induced by IL-2 but not by IFN-gamma. These data demonstrate that IL-2 enhances c-fms mRNA and c-fms glycoprotein expression suggesting that IL-2, by augmenting expression of macrophage CSF-1 receptors, can lead to prolongation of monocyte-mediated tumoricidal activity obtained in the presence of exogenous macrophage CSF-1.

Colony-Stimulating Factors↗
PubMed1990

Lipopolysaccharide, but not IFN-gamma, down-regulates c-fms mRNA proto-oncogene expression in murine macrophages.

In the present study we analyzed the effects of two macrophage activators, bacterial LPS and IFN-gamma, on the expression of the c-fms proto-oncogene in the immortalized murine macrophage cell line ANA-1. ANA-1 cells constitutively expressed significant levels of c-fms mRNA. LPS stimulation induced down-regulation of the expression of c-fms mRNA. In contrast, IFN-gamma did not change c-fms expression. Combined treatment of ANA-1 with IFN-gamma plus LPS resulted in a decrease in c-fms mRNA greater than that induced by LPS alone. Nuclear runoff experiments demonstrated that the down-regulation of c-fms mRNA by LPS or LPS plus IFN-gamma was controlled at a transcriptional level. Moreover, experiments in which c-fms mRNA expression was evaluated after the block of RNA or of protein synthesis did not reveal any difference in c-fms mRNA stability in LPS-treated and in untreated cells. These results demonstrate that LPS does not affect the stability of c-fms mRNA, but it decreases the transcription of the gene.

Animals↗
PubMed1989

A functional protein kinase C is required for induction of 2-5A synthetase by recombinant interferon-alpha A in Daudi cells.

Treatment of Daudi B lymphoblastoid cells with interferon (IFN)-alpha or -beta has been reported (Yap, W. H., Teo, T. S., and Tan, Y. H. (1986) Science 234, 355-358) to cause a transient increase in the level of diacylglycerol, which is the endogenous activator of protein kinase C (PK-C). To assess the role for PK-C in the induction of 2-5A synthetase mRNA and activity by IFN-alpha in Daudi cells, we have examined the effects of PK-C inhibitors and activators. We have found that the PK-C inhibitor, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), strongly inhibits the induction of 2-5A synthetase mRNA and activity by recombinant IFN-alpha A (rIFN-alpha A) and that this inhibition appears to be at a post-transcriptional level. The inhibition by H7 could not be attributed to a generalized decrease in macromolecular synthesis or to inhibition of the binding or internalization of rIFN-alpha A. Moreover, pretreatment of Daudi cells for 24 h with phorbol esters to down-regulate or desensitize PK-C substantially inhibited the subsequent induction of 2-5A synthetase mRNA and activity by rIFN-alpha A. These data suggest that PK-C activity is required for the induction of 2-5A synthetase by rIFN-alpha A. However, phorbol esters, which are potent PK-C activators, did not induce 2-5A synthetase. Taken together, our data indicate that a functional PK-C is required for 2-5A synthetase induction by rIFN-alpha A at a post-transcriptional level in Daudi cells but that activation of PK-C is not sufficient for induction of this enzyme.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMedDate not supplied

IL-6 signals inhibition of cell adhesion in melanoma A375-C6.

IL-6 has been found to be a potent inhibitor of melanoma A375-C6 cell adhesion, in addition to its known action in arresting cells at G1/G0 phase of the cell cycle IL-6 treated melanoma cells were found to round up and to lose the ability to adhere to fibronectin, laminin, collagen, and tenascin over 72 to 96 hours of IL-6 treatment, a time course similar to that seen for cell cycle inhibition. Cell cycle inhibition and loss of adhesion were found, however, to be independent effects of IL-6. Analysis of cell surface integrins indicated significant changes in the expression of several integrins including downregulation of a3 and av beta 5 and upregulation of a3. However, the changes in integrin expression did not correlate with loss of adhesion to relevant ligands. Three A375 melanoma clones varying in metastatic potential also demonstrated inhibition of both cell proliferation and matrix adhesion by IL-6.

Antigens, CD↗