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1.
近年来研究发现真核生物基因组中的许多重复序列以及基因的内含子参与基因表达的调控。在这些重复序列中,有一种广泛分布于基因组中的逆转座子LINE-1,目前发现其对细胞的增殖与分化以及肿瘤的发生起着非常重要的作用,具体表现为影响基因的转录及整个基因组的稳定性、参与X染色体失活及基因组进化等。在正常细胞的分化调控中,基因的激活与沉默具有时间与空间的特异性,实现其“预定”的、有序的、不可逆转的分化过程。主要阐述了逆转座子LINE-1的结构特征和其在基因组中的调控作用及这些作用影响基因表达从而调节生物体的生命活动。研究LINE-1的调控机制对认识细胞的时空调控以及癌症的发生与发展具有重要的价值。 相似文献
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Wood LD Parsons DW Jones S Lin J Sjöblom T Leary RJ Shen D Boca SM Barber T Ptak J Silliman N Szabo S Dezso Z Ustyanksky V Nikolskaya T Nikolsky Y Karchin R Wilson PA Kaminker JS Zhang Z Croshaw R Willis J Dawson D Shipitsin M Willson JK Sukumar S Polyak K Park BH Pethiyagoda CL Pant PV Ballinger DG Sparks AB Hartigan J Smith DR Suh E Papadopoulos N Buckhaults P Markowitz SD Parmigiani G Kinzler KW Velculescu VE Vogelstein B 《Science (New York, N.Y.)》2007,318(5853):1108-1113
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Jones S Zhang X Parsons DW Lin JC Leary RJ Angenendt P Mankoo P Carter H Kamiyama H Jimeno A Hong SM Fu B Lin MT Calhoun ES Kamiyama M Walter K Nikolskaya T Nikolsky Y Hartigan J Smith DR Hidalgo M Leach SD Klein AP Jaffee EM Goggins M Maitra A Iacobuzio-Donahue C Eshleman JR Kern SE Hruban RH Karchin R Papadopoulos N Parmigiani G Vogelstein B Velculescu VE Kinzler KW 《Science (New York, N.Y.)》2008,321(5897):1801-1806
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Y K Fung A L Murphree A T'Ang J Qian S H Hinrichs W F Benedict 《Science (New York, N.Y.)》1987,236(4809):1657-1661
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Most human cancer cells show signs of genome instability, ranging from elevated mutation rates to gross chromosomal rearrangements and alterations in chromosome number. Little is known about the molecular mechanisms that generate this instability or how it is suppressed in normal cells. Recent studies of the yeast Saccharomyces cerevisiae have begun to uncover the extensive and redundant pathways that keep the rate of genome rearrangements at very low levels. These studies, which we review here, have implicated more than 50 genes in the suppression of genome instability, including genes that function in S-phase checkpoints, recombination pathways, and telomere maintenance. Human homologs of several of these genes have well-established roles as tumor suppressors, consistent with the hypothesis that the mechanisms preserving genome stability in yeast are the same mechanisms that go awry in cancer. 相似文献
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Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88 总被引：1，自引：0，他引：1
Inflammation is increasingly recognized as an important component of tumorigenesis, although the mechanisms and pathways involved are not well understood. Tumor development is regulated by products of several modifier genes, but instructions for their tumor-specific expression are currently unknown. We show that the signaling through the adaptor protein MyD88 has a critical role in spontaneous tumor development in mice with heterozygous mutation in the adenomatous polyposis coli (APC) gene. We found that MyD88-dependent signaling controls the expression of several key modifier genes of intestinal tumorigenesis and has a critical role in both spontaneous and carcinogen-induced tumor development. This study thus reveals the important role of an innate immune signaling pathway in intestinal tumorigenesis. 相似文献
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Morrow EM Yoo SY Flavell SW Kim TK Lin Y Hill RS Mukaddes NM Balkhy S Gascon G Hashmi A Al-Saad S Ware J Joseph RM Greenblatt R Gleason D Ertelt JA Apse KA Bodell A Partlow JN Barry B Yao H Markianos K Ferland RJ Greenberg ME Walsh CA 《Science (New York, N.Y.)》2008,321(5886):218-223
To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations. 相似文献
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An integrated genomic analysis of human glioblastoma multiforme 总被引：1，自引：0，他引：1
Parsons DW Jones S Zhang X Lin JC Leary RJ Angenendt P Mankoo P Carter H Siu IM Gallia GL Olivi A McLendon R Rasheed BA Keir S Nikolskaya T Nikolsky Y Busam DA Tekleab H Diaz LA Hartigan J Smith DR Strausberg RL Marie SK Shinjo SM Yan H Riggins GJ Bigner DD Karchin R Papadopoulos N Parmigiani G Vogelstein B Velculescu VE Kinzler KW 《Science (New York, N.Y.)》2008,321(5897):1807-1812
Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs. 相似文献
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Clustering of genes dispensable for growth in culture in the S component of the HSV-1 genome 总被引：43，自引：0，他引：43
The herpes simplex virus 1 genome consists of one long and one short stretch of unique sequences flanked by inverted repeat sequences. The nucleotide sequence and RNA map predict 12 open reading frames designated as US1 through US12 within the short stretch of unique sequences. This paper reports the construction of virus mutants from which US2, US3, or US4 had been deleted that are capable of growth in cell culture. One of the three deleted genes, US4, specifies the viral envelope glycoprotein G. Mutants with deletions in US1, US8, US9, US10, US11, and US12 have been previously reported. The nine genes deleted from this region form two clusters, US1 through US4 and US8 through US12, and encode at least two and possibly more structural proteins. The presence of so many genes dispensable for growth in cell culture suggests several hypotheses regarding their function and evolution. 相似文献
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Activated proto-onc genes: sufficient or necessary for cancer? 总被引：20，自引：0，他引：20
P H Duesberg 《Science (New York, N.Y.)》1985,228(4700):669-677
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Rivera MN Kim WJ Wells J Driscoll DR Brannigan BW Han M Kim JC Feinberg AP Gerald WL Vargas SO Chin L Iafrate AJ Bell DW Haber DA 《Science (New York, N.Y.)》2007,315(5812):642-645
Wilms tumor is a pediatric kidney cancer associated with inactivation of the WT1 tumor-suppressor gene in 5 to 10% of cases. Using a high-resolution screen for DNA copy-number alterations in Wilms tumor, we identified somatic deletions targeting a previously uncharacterized gene on the X chromosome. This gene, which we call WTX, is inactivated in approximately one-third of Wilms tumors (15 of 51 tumors). Tumors with mutations in WTX lack WT1 mutations, and both genes share a restricted temporal and spatial expression pattern in normal renal precursors. In contrast to biallelic inactivation of autosomal tumor-suppressor genes, WTX is inactivated by a monoallelic "single-hit" event targeting the single X chromosome in tumors from males and the active X chromosome in tumors from females. 相似文献
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Loss of cell polarity and tissue architecture are characteristics of malignant cancers derived from epithelial tissues. We provide evidence from Drosophila that a group of membrane-associated proteins act in concert to regulate both epithelial structure and cell proliferation. Scribble (Scrib) is a cell junction-localized protein required for polarization of embryonic and, as demonstrated here, imaginal disc and follicular epithelia. We show that the tumor suppressors lethal giant larvae (lgl) and discs-large (dlg) have identical effects on all three epithelia, and that scrib also acts as a tumor suppressor. Scrib and Dlg colocalize and overlap with Lgl in epithelia; activity of all three genes is required for cortical localization of Lgl and junctional localization of Scrib and Dlg. scrib, dlg, and lgl show strong genetic interactions. Our data indicate that the three tumor suppressors act together in a common pathway to regulate cell polarity and growth control. 相似文献
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Allelotype of colorectal carcinomas 总被引：86，自引：0，他引：86
B Vogelstein E R Fearon S E Kern S R Hamilton A C Preisinger Y Nakamura R White 《Science (New York, N.Y.)》1989,244(4901):207-211
To examine the extent and variation of allelic loss in a common adult tumor, polymorphic DNA markers were studied from every nonacrocentric autosomal arm in 56 paired colorectal carcinoma and adjacent normal colonic mucosa specimens. This analysis was termed an allelotype, in analogy with a karyotype. Three major conclusions were drawn from this analysis: (i) Allelic deletions were remarkably common; one of the alleles of each polymorphic marker tested was lost in at least some tumors, and some tumors lost more than half of their parental alleles. (ii) In addition to allelic deletions, new DNA fragments not present in normal tissue were identified in five carcinomas; these new fragments contained repeated sequences of the variable number of tandem repeat type. (iii) Patients with more than the median percentage of allelic deletions had a considerably worse prognosis than did the other patients, although the size and stage of the primary tumors were very similar in the two groups. In addition to its implications concerning the genetic events underlying tumorigenesis, tumor allelotype may provide a molecular tool for improved estimation of prognosis in patients with colorectal cancer. 相似文献
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Mao JH Kim IJ Wu D Climent J Kang HC DelRosario R Balmain A 《Science (New York, N.Y.)》2008,321(5895):1499-1502
The enzyme mTOR (mammalian target of rapamycin) is a major target for therapeutic intervention to treat many human diseases, including cancer, but very little is known about the processes that control levels of mTOR protein. Here, we show that mTOR is targeted for ubiquitination and consequent degradation by binding to the tumor suppressor protein FBXW7. Human breast cancer cell lines and primary tumors showed a reciprocal relation between loss of FBXW7 and deletion or mutation of PTEN (phosphatase and tensin homolog), which also activates mTOR. Tumor cell lines harboring deletions or mutations in FBXW7 are particularly sensitive to rapamycin treatment, which suggests that loss of FBXW7 may be a biomarker for human cancers susceptible to treatment with inhibitors of the mTOR pathway. 相似文献
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Tumor suppressor genes: the puzzle and the promise 总被引：43，自引：0，他引：43
R Sager 《Science (New York, N.Y.)》1989,246(4936):1406-1412
Tumor suppressor genes are wild-type alleles of genes that play regulatory roles in cell proliferation, differentiation, and other cellular and systemic processes. It is their loss or inactivation that is oncogenic. The first evidence of tumor suppressor genes appeared in the early 1970s, but only within the past few years has a wealth of new information illuminated the central importance of these genes. Two or more different suppressor genes may be inactivated in the same tumors, and the same suppressors may be inactive in different tumor types (for example, lung, breast, and colon). The suppressor genes already identified are involved in cell cycle control, signal transduction, angiogenesis, and development, indicating that they contribute to a broad array of normal and tumor-related functions. It is proposed that tumor suppressor genes provide a vast untapped resource for anticancer therapy. 相似文献
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Retinoblastoma: clues to human oncogenesis 总被引：26，自引：0，他引：26
The retinoblastoma gene can be considered a model for a class of recessive human cancer genes that have a "suppressor" or "regulatory" function. The loss or inactivation of both alleles of this gene appears to be a primary mechanism in the development of retinoblastoma. Such a mechanism is in direct contrast to that of putative human oncogenes which are thought to induce tumorigenesis following activation or alteration. The high incidence of second primary tumors among patients who inherit one inactive retinoblastoma allele also suggests that this cancer gene plays a key role in the etiology of several other primary malignancies. Finally, the observation that extra nonrandom copies of specific chromosomal regions occur in some of these tumors provides circumstantial evidence that an "expressor" gene (possibly an oncogene) may be involved in retinoblastoma development. 相似文献
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Tryptophan operon of Escherichia coli: regulatory behavior in Salmonella typhimurium cytoplasm 总被引：8，自引：0，他引：8
R L Somerville 《Science (New York, N.Y.)》1966,154(756):1585-1587
Hybrids hemizygous for the tryptophan genes were prepared by episomal transfer of an Escherichia coli element into Salmonella typhimurium. Regulation of enzyme production by hybrids carrying wild-type E. coli genes in response to changes in the growth medium occurs in precisely the same manner as in haploid E. coli wild type. Mutant alleles of the anthranilate synhetase gene of E. coli which prevent derepression in E. coli function identically in S. typhimurium. At least one Salmonella tryptophan regulatory gene unlinked to the structural genes is known. Any dijferences which may exist between the tryptophan regulatory genes of E. coli and Salmonella have little effect on the regulation of enzyme formation in hybrids. 相似文献