epidermal-growth-factor and epiderstatin

Topics: Animals; Antibiotics, Antineoplastic; Epidermal Growth Factor; Mice; Mice, Inbred BALB C; Molecular Structure; Piperidones; Pyridones; Stereoisomerism; Structure-Activity Relationship

Epiderstatin, a distinctive glutarimide antibiotic isolated from Streptomyces pulveraceus subsp. epiderstagenes, has been revealed to be a potent inhibitor of the signal transduction of epidermal growth factor (EGF). Epiderstatin inhibited the DNA synthesis induced by various peptide growth factors in a mouse epidermal cell line, BALB/MK, without inhibiting protein tyrosine kinase activity of EGF-receptor or serine/threonine kinase activity of protein kinase C. The 50% inhibitory concentration (IC50) value of epiderstatin for the EGF-stimulated incorporation of [3H]thymidine into BALB/MK cells was about 10 nM. When epiderstatin was added to the quiescent cells simultaneously with EGF-stimulation, the cells did not reenter into the growing cell cycle. The action of epiderstatin proceeded from the overexpression of c-fos and the suppression of c-myc transcription when EGF was added to quiescent BALB/MK cells.

Topics: Actins; Animals; Cell Cycle; Cell Division; Cell Transformation, Viral; DNA; Epidermal Cells; Epidermal Growth Factor; Epidermis; ErbB Receptors; Gene Expression Regulation; Genes, fos; Genes, myc; Keratinocytes; Mice; Mice, Inbred BALB C; Piperidones; Protein Kinases; Protein-Tyrosine Kinases; Pyridones; Signal Transduction; Stimulation, Chemical; Transcription, Genetic

Epiderstatin is a unique glutarimide antibiotic which was found by screening for inhibitors of the signal transduction of epidermal growth factor (EGF). The antibiotic (0.01 microM) was found to reverse the morphology of NRK cells that were infected with a temperature-sensitive mutant of Rous sarcoma virus (srcts-NRK) from the transformed phenotype to the normal phenotype at the permissive temperature (32 degrees C). Epiderstatin did not inhibit the protein kinase activity of p60v-src. The cell cycle progression of src(ts)-NRK cells was blocked at G0/G1 phase, which was caused by the inhibition of biosynthesis of p60v-src but not the transcription of v-src mRNA.

Topics: Animals; Antibiotics, Antineoplastic; Avian Sarcoma Viruses; Biotechnology; Cell Cycle; Cell Division; Cell Line, Transformed; Cell Transformation, Viral; Epidermal Growth Factor; Mutation; Oncogene Protein pp60(v-src); Phenotype; Piperidones; Pyridones; Rats; RNA, Messenger; Temperature

Topics: Antibiotics, Antineoplastic; Circular Dichroism; Epidermal Growth Factor; Piperidones; Pyridones; Spectrophotometry, Ultraviolet; Streptomyces; X-Ray Diffraction

The structure of a novel antibiotic, epiderstatin, was determined as 4-[3-((Z)-3,5-dimethyl-2-oxopiperidin-6-ylidene)-2-oxopropyl]-2, 6-piperidinedione by spectroscopic analyses of 1H NMR, 13C NMR, 1H-1H correlation spectroscopy (COSY), 13C-1H COSY, heteronuclear multiple bond correlation spectroscopy, UV and IR spectra. The antibiotic belongs to the glutarimide antibiotics, however, the characteristic feature of epiderstatin is that it has a piperidone ring instead of a cyclohexanone ring.

Topics: Antibiotics, Antineoplastic; Epidermal Growth Factor; Magnetic Resonance Spectroscopy; Methylation; Molecular Structure; Piperidines; Piperidones; Pyridones; Spectrophotometry, Ultraviolet; Spectrum Analysis

Inhibitors of mitogenic activity induced by epidermal growth factor (EGF) were screened from culture broths of soil microorganisms. A strain of actinomycetes has been found to produce a new glutarimide antibiotic named epiderstatin which inhibits the incorporation of [3H]thymidine into quiescent animal cells stimulated by EGF. Taxonomic studies have revealed that the producing strain belongs to a subspecies of Streptomyces pulveraceus, thus the name, Streptomyces pulveraceus subsp. epiderstagenes was given to this strain. The molecular formula (C15H20N2O4) and UV profile (lambda max 295 nm) of the antibiotic are distinct from other known antibiotics. It inhibited the incorporation of [3H]thymidine into quiescent cells stronger than into growing cells.

Topics: Animals; Antibiotics, Antineoplastic; Cells, Cultured; Chromatography, Gel; Chromatography, High Pressure Liquid; Epidermal Growth Factor; Fermentation; Magnetic Resonance Spectroscopy; Microscopy, Electron, Scanning; Piperidines; Piperidones; Pyridones; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet; Spores, Bacterial; Streptomyces