Biomedical subjects
Publications and source records attributed to I Ben-Porath.
In the November 15 issue of Nature, report that disruption of histone methylation in the fungus Neurospora crassa results in the elimination of DNA methylation. This demonstrates that chromatin structure can pattern DNA methylation and suggests that different epigenetic layers engage in complex crosstalk.
Recent studies have focused on the identification of imprinting centers and on the elucidation of the mechanisms by which they control imprinting. These studies begin to shed light on the means by which imprinting marks are established in the gametes and on the various molecular strategies utilized to execute differential expression of the two parental alleles.
The c-Myc oncoprotein induces cell proliferation and transformation through its activity as a transcription factor. Uncovering the genes regulated by c-Myc is an essential step for understanding these processes. We recently isolated the tumor-associated membrane protein gene, Tmp, from a c-myc-induced mouse brain tumor. Here we show that Tmp is specifically highly expressed in mammary tumors and T-cell lymphomas which develop in c-myc transgenic mice, suggesting that Tmp expression is a general characteristic of c-Myc-induced tumors. In addition, Tmp expression is induced upon serum stimulation of fibroblasts as shown in a time course closely correlated with c-myc expression. We have isolated the Tmp promoter region and identified a putative c-Myc binding element, CACGTG, located in the first intron of the gene. We show here that constructs containing the Tmp regulatory region fused to a reporter gene are activated by c-Myc through this CACGTG element and that the c-Myc-Max protein complex can bind to this element. Moreover, an inducible form of c-Myc, the MycER fusion protein, can activate the endogenous Tmp gene. We also show that Tmp-overexpressing fibroblasts induce rapidly growing tumors when injected into nude mice, suggesting that Tmp may possess a tumorigenic activity. Thus, TMP, a member of a novel family of membrane glycoproteins with a suggested role in cellular contact, is a c-Myc target and is possibly involved in c-Myc-induced transformation.
We have recently characterized a novel mammalian gene family, encoding membrane glycoproteins with four trans-membrane domains. This gene family includes the previously studied PMP22, which is involved in the Charcot-Marie-Tooth neuropathy, and three novel genes: TMP, XMP, and YMP (HGMW-approved symbols EMP1, EMP2 and EMP3, respectively). The Tmp (tumor-associated membrane protein) gene was isolated from a c-myc induced mouse brain tumor and is expressed in several highly proliferative cell types. We have now isolated cDNAs of the mouse Xmp and Ymp genes and determined the chromosomal localization of mouse Tmp, Xmp, and Ymp. Tmp was mapped to mouse chromosome 6, Xmp was mapped to chromosome 16, and Ymp was mapped to chromosome 7. Tmp and Ymp map to paralogous chromosomal regions, whereas Xmp maps to a chromosomal region that is putatively paralogous to a region on chromosome 11, to which Pmp22 was previously mapped. These data suggest that this family of membrane glycoproteins evolved as a result of chromosomal duplications.
To isolate genes involved in tumor formation and in embryogenesis, a subtracted cDNA library was constructed from a c-myc-induced mouse brain tumor. A gene isolated in this screen, named TMP (tumor-associated membrane protein), codes for a putative glycoprotein with four transmembrane domains. The TMP gene was found to be highly expressed in brain tumor cells but not in normal brain. It is also expressed at high levels in undifferentiated embryonic stem cells, but markedly down-regulated in these cells after their differentiation into embryoid bodies. The TMP amino acid sequence bears high homology to the growth arrest specific protein PMP22/GAS-3, which is involved in several human peripheral neuropathies. The expression patterns of the TMP and PMP22 genes in NIH-3T3 fibroblasts were compared at different proliferation states. The results suggest an inverse pattern of expression for the two homologs, TMP expression being high during cell proliferation and PMP22 expression being high during growth arrest. To further characterize the TMP gene we have isolated its human homolog and examined its expression in embryonic and adult tissues. In our search for human sequences homologous to TMP and PMP22, we identified two new genes which we have named XMP and YMP. Thus, we present a novel family of membrane glycoproteins, one member of which is closely associated with proliferation and another with growth arrest.