Biomedical subjects

J Qian

Publications and source records attributed to J Qian.

At least 19 recordsLinked to original sources

PubMed1999

Clinical significance of alterations of chromosome 8 in high-grade, advanced, nonmetastatic prostate carcinoma.

BACKGROUND: Chromosome 8 alterations, including loss of 8p21-22 and gain of 8q24, are commonly observed in prostate carcinoma. We examined whether these alterations are associated with poor prognosis in prostate cancer. METHODS: We used dual-probe fluorescence in situ hybridization and DNA probes for 8p22 (lipoprotein lipase gene), centromere 8 (8cen), and 8q24 (c-myc gene) to determine the corresponding copy numbers in tumor samples from 144 patients with high-grade, advanced (stage III) prostate carcinoma. Cox models were used for multivariate analysis of systemic progression or patient death from prostate cancer. All statistical tests are two-sided. RESULTS: We classified the 8p22, 8cen, and c-myc copy number as normal, loss, and gain. An additional increase (AI) category of c-myc relative to the centromere copy number (i.e., overrepresentation and amplification of c-myc) was also used. Alterations of 8p22 were not statistically significantly associated with either systemic progression or patient death. Alterations of c-myc were associated with both systemic progression (P =.024) and patient death (P =.039); AI of c-myc showed the poorest outcome. We also evaluated the prognostic relevance of the combined 8p22-8cen-c-myc loci anomaly pattern for the following six patterns: normal-normal-normal, loss-any 8cen-normal, loss-gain-gain, gain-gain-gain, non-loss-any 8cen-AI, and loss-any 8cen-AI, where any 8cen is normal, loss, or gain of the chromosome 8 centromere. Patients with the loss-any 8cen-AI pattern had earlier systemic progression (P =.009) and earlier cause-specific death (P =.013) than did patients with other patterns. Multivariate analyses demonstrated that the loss-any 8cen-AI pattern was an independent risk factor for systemic progression (P<.001) and cause-specific death (P =.002). CONCLUSIONS: Genetic alterations of chromosome 8 appear to accumulate in parallel with the progression of prostate carcinomas. AI of the c-myc gene, especially with loss of 8p22, appears to be associated with poor patient prognosis.

Centromere↗

PubMed1999

Activity-dependent modulation of K+ currents at presynaptic terminals of mammalian central synapses.

1. The activity-dependent regulation of presynaptic K+ currents at the CA3-CA1 synapse in the rat hippocampus was investigated during a train of evoked afferent action potentials. The waveforms of presynaptic compound action potentials (cAPs) and presynaptic Ca2+ transients ([Ca2+]pre,t) were measured with fluorescent voltage-sensitive and Ca2+-sensitive indicators in rat brain slices. 2. Under control conditions, presynaptic cAPs and the accompanying [Ca2+]pre,t displayed similar amplitudes for each stimulus, suggesting that there was no cumulative change of K+ and Ca2+ currents during the test train. However, when a subgroup of presynaptic K+ channels was blocked by a low concentration of 4-aminopyridine (4-AP, 40 microM), a significant facilitation of the [Ca2+]pre,t was observed. 3. This phenomenon was not due to a direct action of 4-AP on presynaptic Ca2+ channels, but to cumulative suppression of the K+ conductance as indicated by the corresponding change in waveforms of the cAP and presynaptic fibre volley. The observed facilitation was not an artifact by virtue of increased fibre recruitment, nor was it related to the accumulation of extracellular K+; rather, it was dependent on Ca2+ influx and stimulation frequency. The time course of recovery from facilitation was closely related to the decay of the intracellular Ca2+ concentration. 4. The facilitation was not blocked by a saturating concentration of 4-AP (8 mM) but was reduced during the application of the K+ channel blocker tetraethylammonium (TEA, 10 mM), implicating the involvement of TEA-sensitive K+ channels. Such activity-dependent suppression of presynaptic K+ conductance could lead to excessive transmitter release and might explain the hippocampal epileptiform activity that can be induced by application of 4-AP.

4-Aminopyridine↗

PubMed1999

Upstream stimulatory factor regulates Pdx-1 gene expression in differentiated pancreatic beta-cells.

The homeobox gene Pdx-1 plays a key role in the development of the pancreas. In the adult, however, expression of the Pdx-1 gene is restricted to pancreatic beta-cells and endocrine cells of duodenal epithelium. Recently, the transcription factor, upstream stimulatory factor (USF), has been shown to bind in vitro to a mutationally sensitive E-box motif within the 5'-flanking region of the Pdx-1 gene [Sharma, Leonard, Lee, Chapman, Leiter and Montminy (1996) J. Biol. Chem. 271, 2294-2299]. In the present study, we show that USF not only binds to the Pdx-1 gene promoter but also functionally regulates the expression of the Pdx-1 gene in differentiated pancreatic beta-cells. Adenovirus-mediated overexpression of a dominant negative form of USF2 decreased binding of endogenous USF to the E-box element by approximately 90%. This reduction in endogenous USF binding led to a greater than 50% decrease in Pdx-1 gene promoter activity, which, in turn, resulted in marked reductions in Pdx-1 mRNA and protein levels. Importantly, the lower Pdx-1 protein levels led to a greater than 50% reduction in Pdx-1 binding activity to the A3 element on the insulin gene promoter, and a significant reduction in insulin mRNA levels. Overall, our results show that USF functionally regulates Pdx-1 gene expression in differentiated pancreatic beta-cells and provide the first functional data for a role of USF in the regulation of a normal cellular gene.

Animals↗

PubMed1999

Localization of PS6K to chromosomal region 17q23 and determination of its amplification in breast cancer.

The application of comparative genomic hybridization to the analysis of genetic abnormalities in breast carcinoma has consistently revealed that chromosome region 17q22-24 is a frequent site of gene amplification in this type of cancer. As part of an examination of expressed sequence tags for novel amplified genes in this region, we identified PS6K amplifications in both breast tumor tissues and cell lines. PS6K was localized to 17q23 and encodes a serine-threonine kinase whose activation is thought to regulate a wide array of cellular processes involved in the mitogenic response including protein synthesis, translation of specific mRNA species, and cell cycle progression from G1 to S phase. Northern and Western analyses revealed that amplification of this gene was accompanied by corresponding increases in mRNA and protein expression, respectively. These data represent the first determination of a gene amplification within 17q22-24 in breast cancer and suggest an oncogenic activity for PS6K.

Breast Neoplasms↗

PubMed1999

Mutation and expression analysis of the p73 gene in prostate cancer.

BACKGROUND: p53 is the most highly mutated tumor suppressor gene in human cancers. Recently, p73, a first homologue of p53, was identified and considered to be an imprinted tumor suppressor gene. Thus, we analyzed the possible role of p73 in human prostate cancers. METHODS: We investigated the expression levels and expressed allelotypes and searched for mutations in the p73 gene in 27 primary prostate cancers with matched normal tissues as well as in four prostate cell lines. RESULTS: Allelic expression analysis using polymorphisms in exons 2 and 5 revealed that p73 is biallelically expressed in both normal and tumor tissues, suggesting that p73 is not imprinted in prostate tissues. Quantitative PCR demonstrated that p73 expression is the same in both normal and tumor prostate tissues. Denaturing high-performance liquid chromatography and DNA sequencing revealed that there were no tumor-specific mutations in the p73 gene at the genomic level. CONCLUSIONS: These data indicate that alterations of p73, including mutations, changes in message abundance, and changes in allelic expression, are likely to be rare in early-stage prostate cancer, and that p73 could be a tissue-specific imprinting gene.

DNA Mutational Analysis↗

PubMed1999

Fibro-osseous lesions involving the brain: MRI.

We present the MRI findings in two patients with "fibro-osseous lesions" involving the central nervous system. A left temporal lobe mass was present in one patient and an extra-axial mass at the skull base in the other. In both cases, calcification was present, with low signal intensity on T1- and T2-weighted images.

Adult↗

PubMed1999

Fibro-osseous lesions of the central nervous system: report of four cases and literature review.

Fibro-osseous lesions, also reported as calcifying pseudoneoplasms of the neural axis, are uncommon lesions of the CNS. We report four additional cases: two extraaxial and two intraaxial, in patients ages 33, 47, 49, and 59 years at presentation. Fibro-osseous lesions involving the CNS demonstrate variable proportions of fibrous stroma, bone, palisading spindle to epithelioid to multinucleated cells in association with a highly distinctive, perhaps pathognomonic, chondromyxoid-like matrix often distributed in a nodular pattern. This histopathologically distinctive lesion can be seen in many regions of the neuraxis, often with a dural association, and most commonly along the vertebral column. It appears to be a slow-growing lesion and, with wide excision, the prognosis is excellent. The etiology remains unclear, but the preponderance of data favors a reactive rather than neoplastic process. If this putative pseudotumor is not recognized histopathologically, a neoplastic or infectious differential might result in inappropriate investigations and potentially harmful therapies.

Adult↗

PubMed1999

Modulation of transmitter release by action potential duration at the hippocampal CA3-CA1 synapse.

Presynaptic Ca2+ influx through voltage-dependent Ca2+ channels triggers neurotransmitter release. Action potential duration plays a determinant role in the dynamics of presynaptic Ca2+ influx. In this study, the presynaptic Ca2+ influx was optically measured with a low-affinity Ca2+ indicator (Furaptra). The effect of action potential duration on Ca2+ influx and transmitter release was investigated. The K+ channel blocker 4-aminopyridine (4-AP) was applied to broaden the action potential and thereby increase presynaptic Ca2+ influx. This increase of Ca2+ influx appeared to be much less effective in enhancing transmitter release than raising the extracellular Ca2+ concentration. 4-AP did not change the Ca2+ dependence of transmitter release but instead shifted the synaptic transmission curve toward larger total Ca2+ influx. These results suggest that changing the duration of Ca2+ influx is not equivalent to changing its amplitude in locally building up an effective Ca2+ concentration near the Ca2+ sensor of the release machinery. Furthermore, in the presence of 4-AP, the N-type Ca2+ channel blocker omegaCgTx GVIA was much less effective in blocking transmitter release. This phenomenon was not simply due to a saturation of the release machinery by the increased overall Ca2+ influx because a similar reduction of Ca2+ influx by application of the nonspecific Ca2+ channel blocker Cd2+ resulted in much more inhibition of transmitter release. Rather, the different potencies of omega-CgTx GVIA and Cd2+ in inhibiting transmitter release suggest that the Ca2+ sensor is possibly located at a distance from a cluster of Ca2+ channels such that it is sensitive to the location of Ca2+ channels within the cluster.

4-Aminopyridine↗

PubMed1999

Genetic and chromosomal alterations in prostatic intraepithelial neoplasia and carcinoma detected by fluorescence in situ hybridization.

OBJECTIVE: In this review, we discuss the utility of fluorescence in situ hybridization (FISH) in the determination of genetic and chromosomal alterations in prostate cancer specimens. We also discuss the genetic association between prostatic intraepithelial neoplasia (PIN) and adenocarcinoma as detected by FISH and other techniques. METHODS AND RESULTS: FISH is a commonly used technique for the determination of gene and chromosome dosage. In tissue sections, FISH allows precise histopathologic correlation of multiple foci of normal epithelium, premalignant lesions, and carcinoma within a single specimen, including study of intratumoral heterogeneity. PIN and prostatic carcinoma foci have a similar proportion of genetic changes, but foci of carcinoma usually have more alterations. This supports the hypothesis that PIN is the most likely precursor of prostatic carcinoma. The most common genetic alterations in PIN and carcinoma are: (1) gain of chromosome 7, particularly 7q31; (2) loss of 8p and gain of 8q, and (3) loss of 10q, 16q and 18q. Inactivation of tumor suppressor genes and/or overexpression of oncogenes in these regions may be important for the initiation and progression of prostate cancer. CONCLUSIONS: FISH is a useful technique to determine genetic relationships between cancer and its precursors. PIN and prostatic carcinoma foci have a similar proportion of genetic alterations, suggesting that PIN is often a precursor of prostatic carcinoma. Genes on chromosomes 7, 8, 10, 16 and 18 may play an important role in both initiation and progression of prostatic carcinoma.

Adenocarcinoma↗

PubMed1999

Reversibility of prostatic intraepithelial neoplasia: implications for chemoprevention.

High-grade prostatic intraepithelial neoplasia is the most likely precursor of prostatic adenocarcinoma, according to virtually all available evidence. It has a high predictive value as a marker for adenocarcinoma, and its identification in biopsy specimens of the prostate warrants further search for concurrent invasive carcinoma. Androgen deprivation therapy and radiation therapy decrease its prevalence and extent, suggesting a role in chemoprevention.

Adenocarcinoma↗

PubMed1999

Reduced blood pressure and increased sensitivity of the vasculature to parathyroid hormone-related protein (PTHrP) in transgenic mice overexpressing the PTH/PTHrP receptor in vascular smooth muscle.

PTH-related protein (PTHrP) is produced in vascular smooth muscle, where it is postulated to exert vasorelaxant properties by activation of the PTH/PTHrP type 1 receptor. As a model for studying the actions of locally produced PTHrP in vascular smooth muscle in vivo, we developed transgenic mice that overexpress the PTH/PTHrP receptor (PTHrP-R) in smooth muscle. Oocyte injection with a SMP8-PTHrP-R fusion construct yielded six founder mice. F1 offspring were viable and demonstrated selective overexpression of the SMP8-PTHP-R messenger RNA in smooth muscle-rich tissues. Baseline blood pressure measured in conscious mice by tail sphygmomanometry was significantly lower in the receptor-overexpressing mice than that in controls (117 +/- 4 vs. 133 +/- 3 mm Hg; P < 0.05). In anesthetized animals, iv infusion of PTHrP-(1-34)NH2 caused a significantly greater reduction in blood pressure and total peripheral resistance in transgenic mice than in control animals. Vascular contractility was studied in paired, isometrically mounted aortas from 9-week-old transgenic and wild-type mice. The force of contraction in response to phenlyephrine was not significantly different between transgenic and wild-type mice. However, PTHrP-(1-34) NH2 relaxed aortic vessel preparations from transgenic mice to a greater extent than in controls (77.1 +/- 3% vs. 38.4 +/- 4%; P < 0.001). To determine the impact of overexpression of PTH/PTHrP type 1 receptor and its ligand on the development of the cardiovascular system, double transgenic mice were created by crossing SMP8-PTHrP-R transgenic mice with mice overexpressing PTHrP (SMP8-PTHrP). Double transgenic mice died around day E9 with abnormalities in the developing heart. In conclusion, overexpression of PTH/PTHrP type 1 receptor in vascular smooth muscle of transgenic mice reduces blood pressure, probably through sustained activation of the receptor by endogenous ligand. The cardiovascular defects observed in mice overexpressing both PTHrP and its receptor suggest that PTHrP may play a role in the normal development of the cardiovascular system.

Actins↗

PubMed1999

Targeted overexpression of parathyroid hormone-related protein (PTHrP) to vascular smooth muscle in transgenic mice lowers blood pressure and alters vascular contractility.

PTH-related protein (PTHrP) and its receptor are expressed in vascular smooth muscle cells and are believed to participate in the local regulation of vascular tone. To explore the function of locally produced PTHrP in vascular smooth muscle in vivo, we developed transgenic mice that overexpress PTHrP in smooth muscle using a smooth muscle alpha-actin promoter to direct expression of the transgene. In the PTHrP-overexpressing mice, messenger RNA expression was mainly restricted to smooth muscle-containing tissues. Several founders also expressed the transgene in bone and heart and exhibited striking abnormalities in the development of these tissues. In PTHrP-overexpressing mice, blood pressure was significantly lower than that in wild-type controls (121 +/- 3 vs. 135 +/- 2 mm Hg; P < 0.01). Moreover, the magnitude of the vasorelaxant response to iv infusions of PTHrP-(1-34)NH2 was significantly attenuated in the transgenic animals. A similar desensitization to PTHrP was observed in aortic ring and portal vein preparations. Surprisingly, PTHrP-overexpressing mice were also significantly less responsive to the hypotensive action of infused acetylcholine in vivo and to the relaxant actions of acetylcholine on aortic vessel preparations in vitro. In summary, we have successfully targeted overexpression of PTHrP to the smooth muscle of transgenic mice. When expressed in its normal autocrine/paracrine setting, PTHrP lowers systemic blood pressure and decreases vascular responsiveness to further relaxation by PTHrP and other endothelium-dependent vasorelaxants such as acetylcholine. We postulate that the heterologous desensitization to acetylcholine-induced relaxation in PTHrP-overexpressing blood vessels involves desensitization of second messenger/effector signaling pathways common to PTHrP and acetylcholine.

Actins↗

PubMed1999

Vasorelaxant properties of parathyroid hormone-related protein in the mouse: evidence for endothelium involvement independent of nitric oxide formation.

PTH-related peptide is produced in vascular smooth muscle and is believed to participate in the local control of vascular tone. The recent identification of mid-region PTHrP peptides, as well as the discovery of multiple receptors in blood vessels, raises new questions concerning the mechanisms by which PTHrP relaxes the vasculature. In this study, we examined these mechanisms in two vascular beds of the mouse. PTHrP-(1-34) and PTH-(1-34), but not PTHrP-(38-64) or PTHrP-(38-94), caused concentration-dependent relaxation of pre-contracted aortas and reduced the spontaneous phasic activity of the portal vein. PTHrP and PTH-induced aortic relaxations were largely endothelium dependent, whereas an intact endothelium was not necessary for maximal portal vein relaxation. The endothelium-dependent component of PTHrP and PTH-induced aortic relaxations were unaffected by pretreatment with either L-NNA or indomethacin but were abolished by pretreatment with tetrabutyl ammonium. These results demonstrate that the N-terminal portions of PTHrP and PTH are required for their vasorelaxant activity in the mouse. In addition, maximal relaxant activity of PTHrP and PTH in murine aorta is dependent on the endothelium, which appears to involve the generation of an endothelium-derived hyperpolarizing factor.

Animals↗

PubMed1999

Inhibitor antibody development and T cell response to human factor VIII in murine hemophilia A.

In order to understand better the mechanism of inhibitor formation in hemophilia A patients, we have characterized the immune response to human factor VIII in a murine model of hemophilia A. Mice with severe factor VIII deficiency caused by targeted gene disruptions in exons 16 and 17 were injected intravenously with human factor VIII. Anti-factor VIII was absent or was detected at only very low levels in hemophilic mice of both strains after a single injection of 0.2 microg factor VIII, but it was present in most mice after a second exposure. Subsequent exposures led to high titer anti-factor VIII antibodies in both ELISA and inhibitor assays. A human factor VIII-specific T cell proliferative response was detected with spleen cells obtained three days after a single injection with human factor VIII, before mice had detectable anti-factor VIII antibodies. Subsequent exposures to factor VIII were followed by an increased T cell proliferative response. These studies indicate that murine hemophilia A is a good model for the study of the immune response to human factor VIII, especially the role of the T cell in the early steps in inhibitor antibody formation.

Animals↗

PubMed1999

Beta- and gamma-catenin mutations, but not E-cadherin inactivation, underlie T-cell factor/lymphoid enhancer factor transcriptional deregulation in gastric and pancreatic cancer.

Adenomatous polyposis coli (APC) mutations are present in >70% of colon cancers. The APC protein binds to beta-catenin (beta-cat), a protein first identified because of its role in E-cadherin (E-cad) cell adhesion. In some colon cancers lacking APC defects, mutations in presumptive glycogen synthase kinase 3beta phosphorylation sites near the beta-cat NH2 terminus appear to render beta-cat resistant to regulation by APC and glycogen synthase kinase 3beta. In cells with APC or beta-cat defects, beta-cat is stabilized and, in turn, binds to and activates T-cell factor (Tcf)/lymphoid enhancer factor (Lef) transcription factors. To further explore the role of APC, beta-cat, Tcf, and E-cad defects in gastrointestinal cancers, we assessed gastric and pancreatic cancers for constitutive Tcf transcriptional activity (CTTA). Two of four gastric and two of eight pancreatic cancer lines showed CTTA. One gastric and one pancreatic cancer had mutations in the NH2-terminal phosphorylation sites of beta-cat. The other gastric cancer with CTTA had a missense mutation at serine 28 of gamma-cat, a potential phosphorylation site in this beta-cat-related protein. Although E-cad is an important binding partner for beta-cat and gamma-cat, E-cad inactivation did not result in CTTA. The beta-cat and gamma-cat mutant proteins identified in our studies strongly activated Tcf transcription in vitro, whereas beta-cat mutant proteins with large NH2-terminal deletions had only modest effects on Tcf. Our results suggest a role for Tcf deregulation in gastric and pancreatic cancer, resulting from beta-cat and gamma-cat mutations in some cases and, in others, from yet to be defined defects. Furthermore, these data imply that the consequences of APC and beta-cat mutations are distinct from the effects of E-cad inactivation.

Adenomatous Polyposis Coli Protein↗

PubMed1998

Independent origin of multiple foci of prostatic intraepithelial neoplasia: comparison with matched foci of prostate carcinoma.

BACKGROUND: Prostate carcinoma usually is heterogeneous and multifocal, with diverse clinical and morphologic manifestations. Understanding of the molecular basis for this heterogeneity is limited, particularly for the putative precursor, high grade prostatic intraepithelial neoplasia (PIN). In this study, the authors attempted to determine the genetic relation between multiple foci of PIN and matched foci of carcinoma, and whether they are independent in origin. METHODS: The distribution and prevalence of allelic imbalance at 6 microsatellite polymorphic markers on chromosomes 7q, 8p, 8q, and 18q were examined in 84 microscopically excised PIN foci (mean, 1.6 foci/case) and 95 foci of prostate carcinoma (mean, 1.8 foci/case) from 52 completely embedded, mapped whole mount prostates. RESULTS: PIN contained a lower overall proportion of allelic imbalance than matched prostate carcinoma foci for the 6 polymorphic microsatellite markers (65% vs. 82%), but this difference was not significant. The rate of allelic imbalance in PIN was similar to that in prostate carcinoma at 5 of 6 loci studied; the exception, D18S34 (18q12.2-12.3), had a significantly lower rate of allelic imbalance in PIN than in prostate carcinoma (19% vs. 52%), suggesting that genetic alterations in this chromosomal region may be important in carcinogenesis. Of 22 cases with allelic imbalance in at least 1 focus of PIN and 1 focus of prostate carcinoma, 21 informative cases (95%) showed a similar pattern of allelic imbalance at > or = 1 markers in the matched PIN and prostate carcinoma foci. Significant genetic heterogeneity was observed in both PIN and prostate carcinoma. Allelic imbalance was observed in at least 1 focus in 11 of 25 cases with multiple foci of PIN (44%) and 20 of 25 cases with multiple foci of prostate carcinoma (80%). There was no significant correlation between allelic imbalance and pathologic stage or tumor grade. CONCLUSIONS: Our findings indicate that multiple foci of PIN arise independently within the same prostate. This observation suggests that a field effect underlies prostatic neoplasia. Multiple foci of prostate carcinoma also often arise independently, lending additional support for this hypothesis. The strong genetic similarities between PIN and prostate carcinoma strongly suggest that evolution and clonal expansion of PIN may account for the multifocal etiology of carcinomas.

Aged↗

PubMed1998

Pharmacokinetic interaction between ritonavir and didanosine when administered concurrently to HIV-infected patients.

The effect of coadministration of ritonavir and didanosine (ddI) on the pharmacokinetics of these drugs was investigated in a single-center, three-period, crossover study. Eighteen asymptomatic, HIV-positive men were assigned randomly to 6 different sequences of 3 regimens: ddI (200 mg every 12 hours) alone for 4 days, ritonavir (600 mg every 12 hours) alone for 4 days, and 4 days of ddI with ritonavir under dose-staggering conditions. Although not statistically significant, ritonavir concentrations were slightly higher on average (<10%) with concurrent administration of ddI compared with those of ritonavir alone. In contrast, ddI concentrations were lower with concurrent administration compared with those of ddI alone; maximum concentration and area under the concentration-time curve were reduced by about 15% (p < .05). The ddI elimination rate constant was unaffected by ritonavir, suggesting no change in ddI's systemic metabolism. Adverse events were similar between regimens. The relatively minor changes in ritonavir and ddI pharmacokinetics are probably not clinically relevant; therefore, dosage adjustment of either compound appears unnecessary when administered concurrently. However, the combination regimen of ddI and ritonavir continue to be evaluated clinically.

Adult↗

PubMed1998

FRA7G extends over a broad region: coincidence of human endogenous retroviral sequences (HERV-H) and small polydispersed circular DNAs (spcDNA) and fragile sites.

FRA7G is an aphidicolin-inducible common fragile site at human chromosomal band 7q31.2. This region is frequently altered in a number of different tumor types including prostate, breast, and ovarian cancer. It has also been hypothesized that this region contains an important tumor suppressor gene which is mutated during the development of these cancers or an oncogene which is amplified. We previously used a FISH-based approach to isolate YAC clones which spanned FRA7G. In this report, we describe the isolation and restriction endonuclease mapping of three overlapping P1 clones which cover FRA7G and the region frequently altered in the different cancers. FISH-based analysis of these clones reveals that aphidicolin-induced breakage in the FRA7G region occurs over a region of at least 300 Kb in length. We have also localized a previously sequenced BAC clone to this region. The sequence obtained from this clone reveals the presence of an endogenous retroviral sequence (HERV-H) in the midst of the FRA7G region as well as sequences with homology to small polydispersed circular DNAs (spcDNAs). Thus for the first two cloned common fragile sites, FRA7G and FRA3B, there is an association with both spcDNAs and hot-spots for viral integration.

Base Sequence↗