The proto-oncogene c-myc is the cellular homologue of the transforming sequence carried by the avian myelocytomastosis virus MC29. A growing body of evidence implicates structural and functional alterations in and around proto-oncogenes such as c-myc in tumorogenesis. Here we report that comparison of the structure of myc from a ductal adenocarcinoma of the breast and from normal breast tissue of the same patient (Sc) revealed a tumour-specific rearrangement of one myc locus and amplification of the other myc locus. (For myc reviews see refs 1-4; for myc involvement in breast neoplasia see refs 5-7.) Within the second intron of the rearranged locus was a non-myc sequence with nearly complete homology to a long interspersed repetitive element (a LINE-1 sequence or L1). In this case, the L1 sequence has functioned as a mobile genetic element to produce a somatic mutation.
A human brainstem cDNA library in bacteriophage Agtll was screened under conditions of reduced hybridization stringency with a leukocyte common antigen (LCA) probe that spanned both conserved cytoplasmic domains. cDNA encoding a receptor-linked protein-tyrosinephosphatase (protein-tyrosine-phosphate phosphohydrolase, EC 3.1.3.48), RPTPase a, has been cloned and sequenced. Human RPTPase a consists of 802 amino acids. The extracellular domain of 150 residues includes a hydrophobic signal peptide and eight potential N-glycosylation sites. This is followed by a transmembrane region and two tandemly repeated conserved domains characteristic of all RPTPases identified thus far. The gene for RPTPase a has been localized to human chromosome region 20pter-20q12 by analysis of its segregation pattern in rodent-human somatic cell hybrids. Northern blot analysis revealed the presence of two major transcripts of 4.3 and 6.3 kilobases. In addition to RPTPase a, two other RPTPases (, and y), identified in the same screen, have been partially cloned and sequenced. Analysis of sequence comparisons among LCA, the LCA-related protein LAR, and RPTPases a, A, and y reveal4 the existence of a multigene family encoding different RPTPases, each containing a distinct extracellular domain, a single hydrophobic transmembrane region, and two tandemly repeated conserved cytoplasmic domains.The degree and pattern of phosphorylation of tyrosine residues on cellular proteins are regulated by the opposing activities of protein-tyrosine kinases (PTKases; ATP:protein-tyrosine O-phosphotransferase, EC 2.7.1.112) and protein-tyrosine-phosphatases (PTPases; protein-tyrosine-phosphate phosphohydrolase, EC 3.1.3.48). The structural characteristics and evolution of PTKases as well as their role in the regulation of cell growth have been considered elsewhere (1, 2). More recently, attention has also been focused on the growing family of PTPases. This family includes two types of molecules: (i) low molecular weight proteins such as PTPase 1B (3, 4), T-cell PTPase (5), and rat brain PTPase (6), which contain a single conserved phosphatase domain, and (ii) high molecular weight, receptor-linked PTPases (RPTPases) containing two tandemly repeated conserved domains separated by 56-57 amino acids. Examples of these include the leukocyte common antigen (LCA), also known as CD45 (7,8)
We present here the complete primary structure of human gp330, the human variant of the principal kidney autoantigen causing Heymann membranous glomerulonephritis in rats. The deduced 4655 amino acid residues give a calculated molecular mass of 519636 Da for the mature protein and consists of a probable 25-amino-acid N-terminal signal peptide sequence, an extracellular region of 4398 amino acids, a single transmembrane-spanning domain of 23 amino acids, and an intracellular C-terminal region of 209 amino acid residues. Three types of cysteine-rich repeats characteristic of the low-density lipoprotein receptor (LDLR) superfamily are present in human gp330. In the extracellular region, there are a total of 36 LDLR ligand-binding repeats, comprising four distinct domains, 16 growth factor repeats separated by eight YWTD spacer regions, and one epidermal growth factor-like repeat. No consensus cleavage sequence for the processing endoprotease furin is detected in human gp330. The intracellular tail contains not only two copies of the F(X)NPXY coated-pit mediated internalization signal characteristic of LDLR superfamily members, but also intriguing and potentially functional motifs including several Src-homology 3 recognition motifs, one Src-homology 2 recognition motif for the p8.5 regulatory subunit of phosphatidylinositol 3-kinase, and additional sites for protein kinase C, casein kinase I1 and CAMP-/cCMPdependent protein kinase. There is approximately 77 5% amino acid identity between human and rat gp330 with rninor differences between the extracellular and intracellular regions. Recently gp330 has been implicated in Ca" regulation in the parathyroid, the placenta, and the renal tubule, but its overall physiological and pathological role still remains uncertain.
Casein kinase IO O (CKIO O), a central component of the circadian clock, interacts with and phosphorylates human period protein 1 (hPER1) NeuroReport 5, 951^955]. A mutation in CKIO O causes a shortened circadian period in Syrian Golden hamster. We have now extended our previous studies to show that human casein kinase IN N (hCKIN N), the closest homologue to hCKIO O, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIN N and hCKIO O phosphorylated and caused protein instability of human period 2 protein (hPER2). Immunohistochemical staining of rat brains demonstrates that CKIN N protein is localized in the suprachiasmatic nuclei, the central location of the master clock. These results indicate that CKIN N may play a role similar to CKIO O, suggesting that it may also be involved in regulating circadian rhythmicity by posttranslation modification of mammalian clock proteins hPER1 and 2. ß
PTPG, the gene for protein-tyrosine phosphatase y(PTPy), maps to a region ofhuman chromosome 3, 3p2l, that is frequently deleted in renal cell carcinoma and lung carcinoma. One of the functions of protein-tyrosine phosphatases is to reverse the effect of protein-tyrosine kinases, many of which are oncogenes, suggesting that some proteintyrosine phosphatase genes may act as tumor suppressor genes.
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