No abstract

Deletions in the 8p21-22 region of the human genome are among the most common genetic alterations in prostate carcinomas. Several studies in di erent tumor tissues, including prostate, indicate that there are probably multiple tumor suppressor genes (TSGs) present in this region. To identify candidate TSGs on 8p22 a YAC contig spanning this region was assembled and YAC clones retro®tted with a selectable marker (neo) were transferred into rat prostate AT6.2 cells. Two overlapping YAC clones showed greatly reduced colonyforming e ciency, indicating they may carry a TSG. Two BAC clones encompassing the overlapping region also appeared to exert suppressive e ects on the growth of AT6.2 cells. Database searches for genes mapped to the critical region identi®ed a gene known as FEZ1 (LZTS1) as a potential candidate suppressor gene. Subsequent experiments showed that over-expression of LZTS1 cDNA inhibited stable colony-forming e ciencies of AT6.2, HEK-293 and LNCaP cells. In contrast, LZTS1-transfected Rat-1 and RM1 cells were growthstimulated. Database searches also identi®ed additional isoforms of the LZTS1 mRNA, as well as LZTS1 protein domains reminiscent of those found in transcription factors. Together these data suggest that the LZTS1 gene is involved in the regulation of cell growth and its loss of function may contribute to the development of prostatic carcinomas, as well as other cancers. Oncogene (2001) 20, 4169 ± 4179.

We report the isolation, sequence, and identification of a cDNA encoding the human kinesin light-chain (KLC) protein. The cDNA molecule consisted of 276 nucleotides of 5' untranslated region, the complete coding sequence of 1,710 nucleotides, and 322 nucleotides of 3' untranslated region. It encoded a polypeptide of 569 amino acids and a deduced molecular mass of 64,789 daltons. The predicted secondary internal structure of the KLC molecule consisted of about 27 contiguous repeats, each of approximately 21 amino acid residues, and could be divided into three domains. The amino-terminal domain consisted of heptad repeats typical of the rod domain of several cytoskeletal proteins. The central and carboxy-terminal domains consist of 21-mer repeats. KLC mRNA was expressed in most tissues analyzed. The gene, which was expressed in bacteria and Chinese hamster ovary cells, was provisionally assigned to the long arm of human chromosome 14.

The pesticide rotenone, a neurotoxin that inhibits the mitochondrial complex I, and destabilizes microtubules (MT) has been linked to Parkinson disease (PD) etiology and is often used to model this neurodegenerative disease (ND). Many of the mechanisms of action of rotenone are posited mechanisms of neurodegeneration; however, they are not fully understood. Therefore, the study of rotenone-affected functional pathways is pertinent to the understanding of NDs pathogenesis. This report describes the transcriptome analysis of a neuroblastoma (NB) cell line chronically exposed to marginally toxic and moderately toxic doses of rotenone. The results revealed a complex pleiotropic response to rotenone that impacts a variety of cellular events, including cell cycle, DNA damage response, proliferation, differentiation, senescence and cell death, which could lead to survival or neurodegeneration depending on the dose and time of exposure and cell phenotype. The response encompasses an array of physiological pathways, modulated by transcriptional and epigenetic regulatory networks, likely activated by homeostatic alterations. Pathways that incorporate the contribution of MT destabilization to rotenone toxicity are suggested to explain complex I-independent rotenone-induced alterations of metabolism and redox homeostasis. The postulated mechanisms involve the blockage of mitochondrial voltage-dependent anions channels (VDACs) by tubulin, which coupled with other rotenone-induced organelle dysfunctions may underlie many presumed neurodegeneration mechanisms associated with pathophysiological aspects of various NDs including PD, AD and their variant forms. Thus, further investigation of such pathways may help identify novel therapeutic paths for these NDs.

BackgroundAlpha synuclein (SNCA) has been linked to neurodegenerative diseases (synucleinopathies) that include Parkinson's disease (PD). Although the primary neurodegeneration in PD involves nigrostriatal dopaminergic neurons, more extensive yet regionally selective neurodegeneration is observed in other synucleinopathies. Furthermore, SNCA is ubiquitously expressed in neurons and numerous neuronal systems are dysfunctional in PD. Therefore it is of interest to understand how overexpression of SNCA affects neuronal function in regions not directly targeted for neurodegeneration in PD.ResultsThe present study investigated the consequences of SNCA overexpression on cellular processes and functions in the striatum of mice overexpressing wild-type, human SNCA under the Thy1 promoter (Thy1-aSyn mice) by transcriptome analysis. The analysis revealed alterations in multiple biological processes in the striatum of Thy1-aSyn mice, including synaptic plasticity, signaling, transcription, apoptosis, and neurogenesis.ConclusionThe results support a key role for SNCA in synaptic function and revealed an apoptotic signature in Thy1-aSyn mice, which together with specific alterations of neuroprotective genes suggest the activation of adaptive compensatory mechanisms that may protect striatal neurons in conditions of neuronal overexpression of SNCA.