The CDKN2A locus on chromosome 9p21 contains the p14 ARF and p16 INK4a genes, and is frequently deleted in human neoplasms, including brain tumors. In this study, we screened 34 primary (de novo) glioblastomas and 16 secondary glioblastomas that had progressed from low-grade diffuse astrocytomas for alterations of the p14 ARF and p16 INK4a genes, including homozygous deletion by differential PCR, promoter hypermethylation by methylationspecific PCR, and protein expression by immunohistochemistry. A total of 29 glioblastomas (58%) had a p14 ARF homozygous deletion or methylation, and 17 (34%) showed p16 INK4a homozygous deletion or methylation. Thirteen glioblastomas showed both p14 ARF and p16 INK4a homozygous deletion, while nine showed only a p14 ARF deletion. Immunohistochemistry revealed loss of p14 ARF expression in the majority of glioblastomas (38/50, 76%), and this correlated with the gene status, i.e. homozygous deletion or promoter hypermethylation. There was no significant difference in the overall frequency of p14 ARF and p16 INK4a alterations between primary and secondary glioblastomas. The analysis of multiple biopsies from the same patients revealed hypermethylation of p14 ARF (5/15 cases) and p16 INK4a (1/15 cases) already at the stage of low-grade diffuse astrocytoma but consistent absence of homozygous deletions. These results suggest that aberrant p14 ARF expression due to homozygous deletion or promoter hypermethylation is associated with the evolution of both primary and secondary glioblastomas, and that p14 ARF promoter methylation is an early event in subset of astrocytomas that undergo malignant progression to secondary glioblastoma.

Maternal use of BZD and/or HBRA may increase the risk for preterm birth and low birth weight and cause neonatal symptoms, but does not appear to have a strong teratogenic potential. The tentative association with pylorostenosis and alimentary tract atresia needs confirmation.

No abstract

We previously identi®ed a novel p53-induced mouse gene, wig-1, that encodes a 290 amino acid zinc ®nger protein (Varmeh-Ziaie et al., 1997). Here we have identi®ed and characterized the human homolog of mouse wig-1. The human wig-1 protein is 87% identical to the mouse protein and contains three zinc ®nger domains and a putative nuclear localization signal. Human wig-1 mRNA and protein is induced following activation of wild type p53 expression in our BL41-ts p53 Burkitt lymphoma cells. Wig-1 is also induced in MCF7 cells following treatment with the DNA-damaging agent mitomycin C. Northern blotting detected low levels of wig-1 mRNA in normal human tissues. Fluorescence in situ hybridization mapped wig-1 to human chromosome 3q26.3-27. FLAG-tagged human wig-1 localizes to the nucleus. Ectopic overexpression of human wig-1 inhibits tumor cell growth in a colony formation assay. These results suggest that human wig-1 has a role in the p53-dependent growth regulatory pathway. Oncogene (2001) 20, 5466 ± 5474.

No abstract

Platelet-derived growth factor BB (PDGF BB) is a potent mitogen for fibroblasts as well as many other cell types. Interaction of PDGF BB with the PDGF ␤ receptor (PDGF-␤R) activates numerous signaling pathways and leads to a decrease in receptor expression on the cell surface. PDGF-␤R downregulation is effected at two levels, the immediate internalization of ligand-receptor complexes and the reduction in pdgf-␤r mRNA expression. Our studies show that pdgf-␤r mRNA suppression is regulated by the c-myc proto-oncogene. Both constitutive and inducible ectopic Myc protein can suppress pdgf-␤r mRNA and protein. Suppression of pdgf-␤r mRNA in response to Myc is specific, since expression of the related receptor pdgf-␣r is not affected. We further show that Myc suppresses pdgf-␤r mRNA expression by a mechanism which is distinguishable from Myc autosuppression. Analysis of c-Myc-null fibroblasts demonstrates that Myc is required for the repression of pdgf-␤r mRNA expression in quiescent fibroblasts following mitogen stimulation. In addition, it is evident that the Myc-mediated repression of pdgf-␤r mRNA levels plays an important role in the regulation of basal pdgf-␤r expression in proliferating cells. Thus, our studies suggest an essential role for Myc in a negative-feedback loop regulating the expression of the PDGF-␤R.

Women using antiemetics as a rule have a better delivery outcome than other women, probably due to an effect of a well-functioning placenta, which is associated with NVP. There were no signs of any significant teratogenicity of the drugs studied, but for some drugs the number of exposures was low.

The myc family of genes contains five functional members. We describe the cloning of a new member of the myc family from rat genomic and cDNA libraries, designated B-myc. A fragment of cloned B-myc was used to map the corresponding rat locus by Southern blotting of DNA prepared from rat x mouse somatic cell hybrids. B-myc mapped to rat chromosome 3. We have previously mapped the c-myc to rat chromosome 7 (J. Sumegi, J. Spira, H. Bazin, J. Szpirer, G. Levan, and G. Klein, Nature [London] 306:497-498, 1983) and N-myc and L-myc to rat chromosomes 6 and 5, respectively (S. Ingvarsson, C. Asker, Z. Wirschubsky, J. Szpirer, G. Levan, G. Klein, and J. Sumegi, Somat. Cell Mol. Genet. 13:335-339, 1987). A partial sequence of B-myc had extensive sequence homology to the c-myc protein-coding region, and the detection of intron homology further indicated that these two genes are closely related. The DNA regions conserved among the myc family members, designated myc boxes, were highly conserved between c-myc and B-myc. A lower degree of homology was detected in other parts of the coding region in c-myc and B-myc not present in N-myc and L-myc. A 1.3-kilobase B-myc-specific mRNA was detected in most rat tissues, with the highest expression in the brain. This resembled the expression pattern of c-myc, although at different relative levels, and was in contrast to the more tissue-specific expression of N-myc and L-myc. B-myc was expressed at uniformly high levels in all fetal tissues and during subsequent postnatal development, in contrast to the stage-specific expression of c-myc.