Showing papers by "Kari Alitalo published in 1986"

Oncogene amplification in tumor cells

Abstract: Publisher Summary This chapter summarizes the third mechanism of oncogene activation—oncogene amplification. It illustrates the various ways by which the oncogenic potential of different proto-oncogenes can be activated. Because of the involvement of myc oncogenes in amplifications in a variety of tumors, other lesions that also activate the cellular oncogene c-myc and the aspects of the normal regulation of this oncogene are also described. Since its discovery in drug-resistant eukaryotic cells, somatic amplification of specific genes has been implicated in an increasing variety of adaptive responses of cells to environmental stresses. Experimental work on drug-resistant cells has shown that in the absence of a selection pressure (drug), double minute chromosomes (DMINs) and the amplified genes that they contain are lost, whereas amplified DNA in the form of homogeneously staining regions (HSRs) is retained in the cells. If DMINs and HSRs contain amplified genes that encode drug-resistant or growth-stimulating protein products, it would follow that the more stable chromosomal form, the HSR, confers a greater selective growth advantage for cells. Although DMINs and HSRs have been described predominantly in tumor cells selected for the resistance to cytotoxic drugs, it is also clear that DMINs and HSRs may be present in cancer cells before the start of therapy.

Human ornithine decarboxylase sequences map to chromosome regions 2pter----p23 and 7cen----qter but are not coamplified with the NMYC oncogene.

Abstract: Using a mouse cDNA probe for ornithine decarboxylase (ODC), we have identified and isolated an ODC cDNA clone from a λ gt11 recombinant library prepared from human liver cell mRNA. The 2.0-kb insert of this clone hybridizes with several mouse genomic ODC DNA restriction fragments under conditions of low stringency, but reacts with only few human DNA fragments and a polyA+ RNA species of 2.2 kb under both nonstringent and stringent hybridization conditions. This suggests that, unlike the mouse genome, there are only few ODC genes in the human genome. The human ODC DNA fragments segregate with chromosome regions 2pter→p23 and 7cen→qter in mouse × human somatic cell hybrid clones containing normal, translocated, and deleted human chromosomes. Sequences of the short arm of chromosome 2 containing the NMYC oncogene at 2p23→p24 are often involved in DNA amplification in neuroblastomas and small-cell lung cancers. However, in at least three cases—one neuroblastoma cell line, one neuroblastoma tumor, and one lung carcinoma—the ODC sequences are not coamplified with the NMYC oncogene.

Rearrangement at the 5' end of amplified c-myc in human COLO 320 cells is associated with abnormal transcription.

Abstract: The proto-oncogene c-myc is amplified in sublines of human COLO 320 cells carrying either homogeneously staining chromosomal regions or double minutes. COLO 320 cells carrying homogeneously staining chromosomal regions have 15 to 20 copies of an apparently normal c-myc allele and 1 to 2 copies of an abnormal c-myc allele lacking exon 1 and express high levels of a normal c-myc mRNA 2.5 kilobases in size. COLO 320 cells carrying double minutes have about 25 copies each of the normal allele and the abnormal allele but express preferentially an abnormal c-myc mRNA 2.2 kilobases in size. Nucleotide sequence analyses revealed that the break point of rearrangement resulting in the loss of exon 1 in the abnormal allele lies within a region frequently rearranged in human and murine B-cell tumors.

Activation of c-ras oncogenes by mutations and amplification.

Abstract: About 15% of all human tumours, including carcinomas, sarcomas, melanomas and leukaemias, contain c-ras oncogenes, which can be detected by a variety of methods. The activating lesion in the c-ras oncogenes is most often a point mutation affecting certain critical amino acid residues of its protein product. The clinical significance of c-ras oncogenes is not yet clear.

Tyrosine kinases in control of cell growth and transformation.

Abstract: The growth of normal cells in tissues is strictly controlled, partly through intercellular communication by polypeptide growth factors. Malignantly transformed cells are independent from external growth factors to a certain extent, but their mechanisms for achieving growth autonomy differ from case to case. Several of the oncogene-encoded proteins are known to participate in the hormonal regulation of cell growth (for a recent review on tyrosine kinase oncogenes see ref. 21). Recent advances in molecular biology have shown important mechanisms for cell emancipation from growth regulatory hormonal signaling systems. A few such examples are discussed below.