myc and src oncogenes have complementary effects on cell proliferation and expression of specific extracellular matrix components in definitive chondroblasts.

Abstract

The effects of the avian viral oncogenes src and myc were compared for their ability to alter the differentiated phenotype and the proliferative capacity of definitive chondroblasts. As previously demonstrated, viruses carrying the src oncogene suppressed the synthesis of the chondroblast-specific products, type II collagen and cartilage-specific sulfated proteoglycan. In contrast, infection with MC29 and HB1 viruses, which carry the myc oncogene, did not suppress the synthesis of these normal differentiated cell products, but the infected cells exhibited an increased proliferative potential. The MH2 virus, which carries both the myc and mil oncogenes, both induced the suppression of these chondroblast-specific products and increased cell proliferation. The implications of these results for cooperation between oncogenes and the multi-oncogene models for neoplastic transformation are discussed.Recent experiments have demonstrated that the transformation of primary cells with oncogenes can require the cooperative effects of more than one oncogene (15). The observed effects of oncogene-driven transformation, both in vitro and in vivo, involve alterations in cell morphology and in cell proliferative potential. The alterations in cell morphology are correlated with, and probably caused by, an altered ability to synthesize particular differentiated cell products (8,19). In particular, transformed fibroblasts and chondroblasts exhibit changes in the synthesis of the extracellular matrix and cytoskeletal proteins (1; E. Allebach, D. Boettiger, M. Pacifici, and S. Adams, submitted for publication). These structural proteins are important in determining cell morphology. Individual oncogenes may have their primary cellular effect on only one of these processes. However, since proliferation and differentiation are linked in the normal cellular developmental program, they are not easily separable. To examine the possibility that differentiation and proliferation may be affected separately by different oncogenes, we used the primary chicken embryo chondroblast system. It has been previously demonstrated, with temperature-sensitive mutants, that the expression of the viral src suppresses the synthesis of type II collagen and the cartilage-type sulfated proteoglycan (1, 10, 19). Furthermore, this suppression appears to be controlled primarily at the level of the mRNA (Allebach et al., submitted for publication) and is not mediated by differences in the cell proliferation rate (19). Synthesis of the definitive cell products by chondroblasts is not incompatible with continued cell proliferation, although cell proliferation does decrease as the extracellular proteoglycan-collagen matrix accumulates. Thus, it may be possible to use this system to separate the effects of oncogenes on cell proliferation from their effects on cell differentiation.There is increasing evidence in support of the proposition that myc has its primary cellular effect on the cell cycle (2,23). In hematopoietic cell cultures, the MC29 virus carrying the myc g...

Prognostic Markers in Chondrosarcoma: Evaluation of Cell Proliferation and of Regulators of the Cell Cycle

“…Early reports had im plicated myc and src oncogenes in the proliferation and synthesis of speci® c matrix com ponents in chondroblasts. 29 65 O ur data supported the usefulness of the proliferation index (M IB -1) as a signi® cant prognostic indicator for chondrosarcom a: a higher proliferation index was asso ciated with a lower event-free survival (p . 0.01).…”

Expression of c-src in cultured human neuroblastoma and small-cell lung carcinoma cell lines correlates with neurocrine differentiation.

“…However, RSV infection of chicken fibroblasts in vivo or in vitro will not give rise to infinitely growing heteroploid lines (43), a feature commonly associated with malignant tumors. Alema et al (3) observed that transformation by pp6O -src is more similar to disturbed differentiation than to malignant cell conversion. In spite of certain differences in the biology of the c-src and v-src proteins, the possibility remains that both essentially affect regulation of differentiation.…”

Interleukin-1 beta-modulated gene expression in immortalized human chondrocytes.

“…The reexpression of the chondrocyte phenotype in subcultured cells can be induced by suspension culture on or within agarose or by use of serum-free defined medium (4)(5)(6). Studies in embryonic quail and chick chondrocytes demonstrated the potential of v-src and v-myc oncogenes to generate cell lines of high proliferative capacities that retained at least some differentiated chondrocyte properties (7,8). Attempts to establish immortalized chondrocyte lines from murine sarcoma virus-transfected rat chondrocytes (9), simian virus 40 (SV40)'-transfected rabbit chondrocytes (10), and human chondrosarcomas (11,12) have resulted in cells that express cartilage-specific proteoglycans but little or no type II collagen.…”