Collectively, the endothelins and their receptors--referred to as the endothelin (ET) axis--have key physiological functions in normal tissue, acting as modulators of vasomotor tone, tissue differentiation, development, cell proliferation and hormone production. Based on new data, the ET axis also functions in the growth and progression of various tumours. Preliminary results from clinical trials, such as those with atrasentan--an ET(A)-receptor antagonist--in prostate cancer, are encouraging. The place of ET-receptor antagonists in cancer therapy for a range of malignancies merits further investigation.

N-myc, a cellular gene related to the c-myc proto-oncogene, was originally identified on the basis of its very frequent amplification and overexpression in a restricted set of tumours, most notably human neuroblastomas. That N-myc may have a causal role in the genesis of these tumours is suggested by the observation that in the rat embryo fibroblast co-transformation assay it has a transforming potential similar to that of c-myc. The apparent structural and functional homology of N-myc and c-myc suggests that they may be members of the same protooncogene family. However, despite these apparent similarities, expression of the two genes appears to be dramatically different with respect to tumour specificity, as well as tissue and developmental stage specificity. To further elucidate the common and unique aspects of N-myc and c-myc gene structure and function in normal and transformed cells, we have determined the organization of human N-myc and the nucleotide sequence of its messenger product, and we report here that N-myc and c-myc have a similar intron/exon structure and that their protein products share regions of significant homology.

Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to intimal hyperplasia during atherosclerosis and restenosis, but the endogenous cell cycle regulatory factors underlying VSMC growth in response to arterial injury are not well understood. In the present study, we report that downregulation of cyclin-dependent kinase 2 (cdk2) activity in serum-deprived VSMCs was associated with the formation of complexes between cdk2 and its inhib-

N-myc, a cellular gene bearing homology to the c-myc protooncogene, is frequently amplified and overexpressed in a highly restricted set of related tumors, most notably neuroblastomas and retinoblastomas. We have examined the possibility that N-myc may play a causal role in the genesis of these tumors by defining its ability to transform primary cells in tissue culture. Using an N-myc expression construct capable of producing constitutively deregulated levels of full-length murine N-myc mRNA, we demonstrate that a deregulated N-myc gene can cooperate with the activated Ha-ras oncogene to cause tumorigenic conversion of normal embryonic fibroblasts in a manner indistinguishable from the deregulated c-myc oncogene. Cell lines established from Nmyc/ras-transformed foci express high levels of the N-myc gene, and such lines are similar to c-myc/ras transformants in their ability to grow in soft agar and cause tumors in syngeneic rats. These results illustrate that N-myc does encode a c-myc-like transforming activity and that this transforming activity is not specific for the very restricted set of tumors in which N-myc is normally amplified or overexpressed.The cellular protooncogene c-myc appears to be involved in the growth and division of a wide variety of normal cells (1-5). Deregulation of c-myc expression has been noted in a large number of different tumors (6-12), suggesting that aberrant c-myc expression can contribute to the development of neoplasia. Biological test systems, in which constitutively deregulated c-myc genes were introduced into cells in culture or into transgenic mice, have verified that altered c-myc expression can play a direct role in the development of malignant transformation (13-15). For example, the malignant transformation ofprimary rat embryo fibroblasts (REFs) requires the cooperative actions of an overexpressed c-myc gene and a mutant ras oncogene (either Ha-ras or N-ras) (13). It is thought that the two oncogenes provide distinct transforming functions, with the c-myc gene satisfying an "establishment" or "immortality" requirement and the ras gene conferring morphological transformation and loss of contact inhibition. Two viral oncogenes, adenovirus EJA and polyoma virus large T, and a single cellular gene, p53, have the capability to substitute for c-myc in a primary cell transformation assay, although the p53 gene appears much weaker than c-myc in its ability to compare with ras (13,(16)(17)(18)(19).N-myc is a cellular gene bearing DNA sequence homology to c-myc. It is frequently amplified and overexpressed in a highly restricted set of related tumors, most notably neuroblastomas and retinoblastomas (20)(21)(22)(23)(24)(25). Furthermore, N-myc gene amplification in primary neuroblastomas correlates with both tumor stage and the ability of these tumors to grow in vitro as established cell lines (24). Here we verify that altered N-myc expression can play a direct role in tumor development by demonstrating that an N-myc expression construct can cooperate with the activated H...

While tumor suppressor genes at 3p (VHL), 13q (RB), and 17p (p53) have been identified, altered genes at other loci on 3p and on 8p have not yet been characterized. Furthermore, the genotype at these loci for squamous cell carcinoma of the upper aerodigestive tract has prognostic importance and may identify the patients who should receive the most aggressive treatment.