Gene/Protein Disease Symptom Drug Enzyme Compound
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Replication of the IncI alpha plasmid ColIb-P9 requires the repZ gene, which encodes an essential, unstable initiator protein termed RepZ. Although many functional features of the ColIb-P9 replicon resemble those of structurally unrelated IncFII plasmids R1 and NR1, the role of transcription of repZ towards the replication origin is poorly understood. Using a series of deletion and substitution mutants of the ColIb-P9 replicon, we found that RepZ prefers to act in cis and that a spacer sequence between repZ and the origin is required for replication. This spacer element, referred to as CIS, retained strong transcription terminator activity. Efficient transcription terminators, whether Rho-dependent or -independent, were capable of replacing CIS function for in vivo replication; ColIb-P9 replicated better as transcription terminated more efficiently within CIS. When the CIS element was substituted for by a strong Rho-dependent terminator, such as lambda tR1 or E. coli trp t', in vivo replication of these recombinant replicons became dependent on the Rho factor, in contrast to the authentic ColIb-P9 replicon.
Mol Microbiol 1995 Jul
PMID:A transcription terminator signal necessary for plasmid ColIb-P9 replication. 749 78

Using polymerase chain reaction amplification of microsatellite regions in DNA from 11 epithelial dysplasias of the esophagus and 21 early squamous cell carcinomas, we were able to detect frequent loss of heterozygosity (LOH) on chromosomes 3p21.3 and 9q31 even in low-grade dysplasias. In contrast, we observed frequent LOHs on chromosomes 9p22 and 17p13 (TP53 locus) only in high-grade dysplasias and carcinomas, but not in any low-grade dysplasias. Analysis of LOH at the same four chromosomal regions in DNA of five additional minimal carcinomas and accompanying dysplastic lesions revealed loss of alleles at the loci on 3p21.3 and 9q31 throughout various degrees of dysplasia and carcinoma; again, LOHs on 9p22 and 17p13 occurred only in high-grade dysplasia and carcinoma in situ. Our results indicated that inactivation of putative tumor suppressor genes on 3p21.3 and 9q31 may be early genetic events during esophageal carcinogenesis, and that additional genetic alterations on 9p22 and 17p13 probably play roles in progression.
Hum Mol Genet 1994 Nov
PMID:Accumulation of genetic alterations during esophageal carcinogenesis. 787 13

The efficiency of the in situ polymerase chain reaction (PCR) for the detection of human papillomavirus (HPV) DNA sequences in 20 cervical biopsies fixed with buffered formalin, paraffin-embedded and revealed negatively by conventional in situ hybridization (ISH) has been investigated. The biopsies were classified histologically into condylomata acuminata without dysplasia, cervical intraepithelial neoplasia and carcinoma in situ. Amplified HPV DNA was performed after an optimal proteolytic digestion using one pair of consensus oligonucleotide primers located in the L1 ORF of HPV 6 and ISH was carried out after the PCR assay with a cocktail of biotinylated HPV probes. Viral DNA was detected in 100% of high grade squamous intraepithelial lesions (SIL) and in 50 to 60% of low grade SIL. The high sensitivity of the in situ PCR applicable to paraffin-embedded archival biopsies facilitated the detection of cells poorly reactive by conventional ISH. In situ PCR appeared clearly an efficient tool to investigate HPV infection in tissue sections.
Mol Cell Probes 1994 Oct
PMID:Detection of human papillomavirus by in situ polymerase chain reaction in paraffin-embedded cervical biopsies. 787 28

Plasma 17-hydroxyprogesterone (17-OH-P) was determined by two commercially available immunoassay kits, a radioimmunoassay (RIA) (OHP-CT, CIS) and an enzyme-immunoassay (EIA) (Serozyme 17 alpha-OH-progesterone, Serono). The determination by RIA was performed according to two procedures, directly on plasma or on a crude plasma extract, whereas that by EIA used only the second procedure. These determinations were carried out in 27 infants below 1 year of age and in 33 women in the follicular phase of the menstrual cycle. The results were compared to those obtained by an in-home RIA (RIA-FRH) which includes an extraction step followed by chromatography on Sephadex LH 20 column. The levels observed were overestimated by both kits. In infants, interference from 17-hydroxy-pregnenolone (17-OH-5P) sulfate occurred when the RIA (CIS) kit was used directly on plasma samples. Using plasma extracts, 17-OH-5P interfered with EIA (Serono) in the infant group and with the RIA (CIS) in the second group. The two kits do not appear to be adequate for 17-OH-P determination at least in infants and in women in the follicular phase of the menstrual cycle.
J Steroid Biochem Mol Biol 1994 Aug
PMID:Plasma 17-hydroxyprogesterone determination with two commercial immunoassays. 804 50

Structural alterations of p53 and overexpression of the p53 protein are found in a large proportion of human cancers. In this study, we examined the frequency of p53 mutations and p53 overexpression in squamous cell carcinomas (SQCC) of head and neck. Expression of p53 was detected by immunochemistry (IHC) with monoclonal antibodies defining three distinct epitopes: PAb421 (species cross-reactive epitope on normal and mutated p53), PAb1801 (epitope on normal and mutated human p53), and PAb240 (conformational epitope of mutated p53 and denatured normal p53). Genetic alterations of p53 were identified by single-strand conformational polymorphism (SSCP) analysis and DNA sequencing in selected cases. IHC assays revealed nuclear p53 immunostaining in 53% of cases (32 of 60) with PAb1801, 38% (23 of 60) with PAb421, and 32% (19 of 60) with PAb240. Cases positive with PAb421 or PAb240 were also positive with PAb1801, whereas PAb421 and PAb240 identified overlapping but distinct tumor subsets. Areas of carcinoma in situ present in the tumor specimens showed nuclear p53 immunostaining in 11 of 26 cases. SSCP analysis for exons 5-9, the most common sites of p53 abnormalities, revealed mutations in 26% (15 of 58) of the evaluable cases. Comparison of the SSCP results with the IHC results for PAb1801 identified 11 cases that were positive by both methods, 4 cases with p53 mutations that were negative by IHC, 20 cases positive by IHC but without detectable p53 mutations, and 23 cases negative by both methods. IHC with PAb240, which is thought to be specific for mutated p53, was positive in 9 cases with demonstrable p53 mutations and in 9 cases with no detectable mutations. DNA sequence analysis of nine tumors identified point mutations, nonsense mutations, and frame-shift mutations. In conclusion, our study shows that p53 overexpression in SQCC of head and neck as detected by IHC is a frequent finding, and that overexpression is associated with common types of p53 mutations in some cases. However, IHC identifies p53 overexpression in some tumors with apparently normal SSCP patterns and, conversely, tumors with nonsense or frameshift mutations may not express any p53 detectable by IHC.
Diagn Mol Pathol 1994 Jun
PMID:Overexpression of p53 protein in squamous cell carcinomas of head and neck without apparent gene mutations. 806 93

The surface water sources of some CIS territories have been screened for cholera toxin genes by the polymerase chain reaction. The vct-genes have been found in the majority of water samples indicating the presence of noncultivated vibrio cholerae cells of an epidemiologic significance. The bacteriological methods failed to isolate the active causative agent of cholera. Additional criteria are proposed for epidemiological typing of territories for cholera. The absence of long deletions or insertions in the vct-genes of noncultivated cholera vibrios has been shown in comparison with analogous gene of the active causative agent of cholera.
Mol Gen Mikrobiol Virusol
PMID:[A possible mechanism for the endemicity of modern cholera (the role of noncultivated forms of Vibrio cholerae 01)]. 830 10

Dynamins are GTPases which support receptor-mediated endocytosis and bind to several tyrosine kinase receptor-associated proteins known to mediate cell proliferation and differentiation. We have recently established that dynamin expression correlates with normal neuronal (Torre et al., J. Biol. Chem., 269 (1994) 32411-32417) and acinar pancreatic cell differentiation (Cook et al., Mol. Biol. Cell, 6 (1995) 405a). To begin to understand the role of dynamin in neoplastic pancreatic cell differentiation, we have followed the expression of this protein by immunohistochemistry during the development of pancreatic tumors in a mancozeb-nitrosomethylurea (NMU)-based carcinogenesis model recently developed in our laboratory (Monis and Valentich, Carcinogenesis, 14 (1993) 929-933). After a single intraperitoneal injection (50 mg/g body wt) of this carcinogen, rats fed with mancozeb develop pancreatic focal acinar hyperplasia (FACH), dysplastic foci (DYF) displaying acinar-like and ductular-like structures, and ductular-like carcinoma in situ (CIS). After histochemical staining using a monoclonal anti-dynamin antibody, high levels of this protein are consistently observed in well-differentiated acinar tumors (FACH). In contrast, dynamin immunoreactivity is almost undetectable in more advanced lesions showing a ductular-like phenotype (ductular-like DYF and CIS). This change in the expression pattern of dynamin during the progression of acinar into ductular-like DYF and CIS lesions correlates with recent findings from our laboratory showing a differential expression pattern for dynamin in pancreatic cells during embryonic development, with ductular-like precursor cells expressing low levels of this protein. Based upon these results, we conclude that more advanced ductular-like neoplastic cells induced by the carcinogen NMU in rat pancreas behave phenotypically like pancreatic precursor cells in their pattern of expression for dynamin.
 ...
PMID:Expression of dynamin immunoreactivity in experimental pancreatic tumors induced in rat by mancozeb-nitrosomethylurea. 860 75

Twenty-nine samples from 28 cases of vulvar squamous cell carcinoma, of which 13 fulfilled the criteria of the bowenoid subtype (mean age 45 years, range 31-68) and 16 of the usual subtype of invasive squamous cell carcinoma (ISCC) (mean age 67.5 years, range 34-83) were investigated for human papillomavirus (HPV) DNA, TP53 alterations, and mdm2 and bcl-2 gene product deregulation. Microscopically all the bowenoid subtype cases (group I) showed a high-grade intraepithelial (VIN 3, carcinoma in situ) lesion associated with early invasive carcinoma in six cases and overt invasive carcinoma in one. By contrast, no evidence of early carcinoma was present in the ISCCs (group II). By in situ hybridization and/or Southern blot hybridization or polymerase chain reaction (PCR), HPV DNA was detected in all cases of group I and in four of 16 cases (25%) of group II, two only by Southern blot after PCR. By single-strand conformation polymorphism and immunocytochemistry only wild-type TP53 and absence of detectable p53 product, respectively, were found in all cases of group I, i.e., in high-risk HPV-positive carcinomas, whereas mutations and/or p53 overexpression accounted for 75% in group II, i.e., in mainly HPV-negative carcinomas. The TP53 gene mutations observed in invasive carcinomas were significantly related to node-positive cases (p = 0.04). Taken together and in agreement with in vitro data, these results support the view that an alteration of TP53, gained either by interaction with viral oncoproteins or by somatic mutations, is a crucial event in the pathogenesis of vulvar carcinomas, but that TP53 mutations are mainly associated with disease progression. Finally, a preliminary immunocytochemical analysis seems to speak against the possible involvement of both MDM2 and BCL-2 gene products in the development of vulvar carcinoma.
Diagn Mol Pathol 1995 Dec
PMID:Papillomavirus, p53 alteration, and primary carcinoma of the vulva. 863 79

During standard registration of incoming surgery specimens, loss of registration numbers may occur. In our laboratory two series of small bladder biopsies (numbered I-V and I-VI, respectively), obtained from two patients, were given the same laboratory registration number. The biopsies were of similar size and embedded in paraffin. Thus, five pairs of Roman-numbered paraffin blocks had the same laboratory registration numbers. The histological findings in several biopsies were similar, some showing carcinoma in situ. Only from biopsy number VI was the identity retained, and this specimen could be used as a reference. We used polymerase chain reaction (PCR)-driven microsatellite marker analysis to identify the specimens using five different microsatellite markers. Within 48 h, two different banding patterns were revealed, allowing us to distinguish the two series. In addition, in one biopsy which showed carcinoma in situ of the bladder, microsatellite instability was observed while in none of this patient's other biopsies containing carcinoma in situ could this phenomenon be detected, which may indicate intratumor heterogeneity or multifocality. In conclusion, it is possible to solve the problem of mixing up small paraffin-embedded biopsies by using microsatellite marker PCR.
Diagn Mol Pathol 1995 Dec
PMID:Rapid identification of mixed up bladder biopsy specimens using polymorphic microsatellite markers. 863 86

To confirm that the hamster cheek-pouch carcinogenesis model reflects development of human squamous cell carcinoma (SCC), we determined if and when p53 mutations occur in the development of SCC in this model by using immunohistochemical staining and polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis plus direct DNA sequencing. Twenty-four hamster cheek-pouches were treated with a solution of 0.5% 7,12-dimethylbenz[a]anthracene in mineral oil three times a week for 16 wk. The malignant endophytic and exophytic tumors induced with this protocol are preceded by a sequence of premalignant lesions such as hyperplasia with or without dysplasia and carcinoma in situ, similar to the development of this cancer in humans. For this study, p53 protein accumulation was evaluated by immunostaining of various hamster cheek-pouch exophytic and endophytic SCCs as well as flat dysplastic hyperplasia and carcinomas in situ. A moderate percentage (33.3%) of exophytic lesions and most endophytic carcinomas (90%) showed positive p53 staining. In addition we also found p53-positive staining in a number of preneoplastic lesions, including areas of focal hyperplasia, dysplastic hyperplasia, and carcinomas in situ. To determine whether the alterations in p53 staining were due to p53 gene mutation, we used PCR-SSCP analysis and direct sequencing. PCR products corresponding to exons 5a, 6, 7, and 8 from 40 tumors with the highest percentage of p53-stained cells were analyzed. We detected shifted bands in 17 lesions. Direct sequencing of eight selected shifted bands revealed four mutations, including two G-->T transversions in codons 216 (tumor #1) and 252 (tumor #2) and one G-->C transversion in codon 282 (tumor #3). Tumor #4 contained a frameshift mutation in codon 251. These mutations are consistent with those reported in many human cancers. Therefore, we concluded that in the hamster cheek-pouch model, p53 protein accumulation occurs frequently and early in carcinogenesis, as it does in human SCCs, and some of these p53 alterations are due to p53 gene mutations. These findings may help us better define the mechanisms of carcinogenesis in the hamster cheek-pouch model, and p53 alterations may be an early biomarker of progression for chemoprevention studies.
Mol Carcinog 1996 Aug
PMID:p53 alterations in chemically induced hamster cheek-pouch lesions. 878 62


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