Biomedical subjects

B Westermark

Publications and source records attributed to B Westermark.

275 records · Page 16Linked to original sources

PubMedDate not supplied

Antibodies against platelet-derived growth factor inhibit acute transformation by simian sarcoma virus.

A clue to the molecular mechanism of neoplastic transformation was provided by the finding of a near identity in amino-acid sequence between the platelet-derived growth factor (PDGF) B-chain and a region in the transforming protein, p28sis, of simian sarcoma virus (SSV), an agent that causes sarcomas and gliomas in experimental animals. This finding infers a direct link between the molecular biology of normal mitogenesis and oncogenesis since it suggests that the transforming activity of SSV is caused by a growth factor. Although PDGF agonist activity has been isolated from conditioned medium of SSV-transformed cells, it is not clear whether infection of responsive cells by SSV leads solely to autocrine stimulation of growth by a secreted PDGF-like factor or whether other, possibly intracellular, activities of p28sis or its processed products contribute to the transformation. To distinguish between these possibilities, we have studied the effect of anti-PDGF antibodies on acute SSV-transformation, and report here that these antibodies inhibit both proliferation and SSV-induced morphological changes in human diploid fibroblasts.

Antibodies↗

PubMedDate not supplied

A human osteosarcoma cell line secretes a growth factor structurally related to a homodimer of PDGF A-chains.

Platelet-derived growth factor (PDGF), as purified from fresh human platelets, is a protein of relative molecular mass (Mr) 30,000 composed of two disulphide-linked subunit chains of similar size, named A and B (ref. 1). The dimer structure of PDGRF seems to be important for its biological effects, as reduction irreversibly inactivates the factor; it is not known, however, whether PDGF exists as a heterodimer or as a mixture of homodimers. Amino-acid sequence analysis has revealed that the A- and B-chains of human PDGF are related to each other, and that the B-chain is almost identical to part of the v-sis gene product of simian sarcoma virus (SSV). There is experimental evidence that a PDGF-like protein is indeed operational in SSV-induced transformation and the biologically active v-sis product is probably structurally similar to a putative dimer of PDGF B-chains. PDGF-like growth factors and/or a 4.2-kilobase (kb) c-sis transcript are present in several transformed mammalian cell lines and in certain nontransformed cells; cloned c-sis complementary DNA from human T cells transformed with human T-lymphotropic virus (HTLV) or from human endothelial cells contains the coding sequence for a putative PDGF B-chain precursor, but apparently lacks PDGF A-chain sequences. We have previously partially purified and characterized a PDGF-like growth factor from U-2 OS cells (osteosarcoma-derived growth factor, ODGF) and shown that this factor has structural, functional and immunological characteristics in common with PDGF. We describe here a procedure for the preparation of homogeneous ODGF, and provide evidence that this factor, which binds to the PDGF receptor, has a structure similar to a homodimer of PDGF A-chains.

Cell Line↗

PubMedDate not supplied

cDNA sequence and chromosomal localization of human platelet-derived growth factor A-chain and its expression in tumour cell lines.

The amino-acid sequence of the precursor of the human tumour cell line-derived platelet-derived growth factor (PDGF) A-chain has been deduced from complementary DNA clones and the gene localized to chromosome 7. The protein shows extensive homology to the PDGF B-chain precursor. Expression of the PDGF A-chain gene is independent of that of the PDGF B-chain in a number of human tumour cell lines, and secretion of a PDGF-like growth factor of relative molecular mass 31,000 correlates with expression of A- but not B-chain messenger RNA.

Base Sequence↗

PubMedDate not supplied

Possible positive autocrine feedback in the prereplicative phase of human fibroblasts.

The growth of normal diploid fibroblasts is generally thought to be tightly controlled by exogenous growth factors such as platelet-derived growth factor (PDGF) and epidermal growth factor (EGF). Subversion of a growth factor pathway at a regulatory point is considered to be a key event in neoplastic transformation and tumorigenesis. Thus, simian sarcoma virus has acquired the gene encoding the B-chain of PDGF and there is direct experimental proof that SSV-transformation is mediated by a PDGF-like growth factor. There is accumulating evidence that PDGF-like molecules are also synthesized and released by certain normal cells, suggesting an important role of cellularly produced PDGF in development and tissue regeneration. We now present evidence that a transient expression of the gene encoding the PDGF A-chain, and the synthesis and release of functional A-chain homodimers, is an early event in the prereplicative phase of normal human foreskin fibroblasts exposed to PDGF or EGF. Since these cells are PDGF-responsive, the results imply the existence of a positive autocrine signal that may serve as an amplifier of the mitogenic response under certain conditions.

Cell Division↗

PubMedDate not supplied

Induction of complete and irreversible damage to malignant glioma cells by L-2,4 diaminobutyric acid.

L-2,4 Diaminobutyric acid (DAB), a non-physiological amino acid, induced an irreversible injury to human malignant glioma cells when incubated for 24h at an amino acid concentration of 6 mmol/l at 37 degrees C. The same treatment of the human glia cells did not result in any cellular damage; not even a concentration as high as 20 mmol/l of the amino acid under the same incubation conditions did affect these cells. However, a further increase in amino acid concentration above that level resulted in a gradual loss of viability among the human glia cells. An experimentally induced rat glioma cell line was also affected by DAB, although displaying less sensitivity than the human glioma cells, and complete cellular destruction was achieved at 16 mmol/l of DAB, i.e. well below the critical concentration for human glia cells. The destructive effect by DAB was pH-sensitive. The N-methylated analogue of a - amino-isobutyric acid exerted a specific inhibitory action on DAB activity, but other amino acids were also inhibitory to various degrees at higher concentrations. Future clinical applications in the treatment of malignant brain tumours in man are discussed.

Aminobutyrates↗