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Biomedical subjects

C M Croce

Publications and source records attributed to C M Croce.

At least 73 records · Page 4Linked to original sources
PubMed1999

Bdp, a new member of a family of DNA-binding proteins, associates with the retinoblastoma gene product.

We have cloned a gene, BDP, encoding a protein with homology to the retinoblastoma-binding proteins Rbp1 and Rbp2. It also has homology to DNA-binding proteins such as Bright, a B-cell-specific trans-activator, and the Drosophila melanogaster dead ringer gene product. Like MyoD, Bdp binds to the COOH-terminal region of pRb through its conserved region and to hypophosphorylated pRb. It also binds to the MAR of the immunoglobulin heavy-chain locus. Thus Bdp may contribute to the transcriptional regulation of genes involved in differentiation and tissue-specific expression.

Amino Acid Sequence↗
PubMed1999

The tumor-suppressor gene FHIT is involved in the regulation of apoptosis and in cell cycle control.

Alteration of the FHIT (fragile histidine triad) gene occurs as an early and frequent event in lung carcinogenesis. FHIT gene transfer into lung cancer cell line H460 lacking Fhit protein expression resulted in reversion of tumorigenicity. To gain insight into the biological function of FHIT, we compared the H460 cell line with its Fhit transfectants (H460/FHIT). A significant inhibition of cell growth was observed in H460/FHIT cells. The analysis of apoptosis by in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling revealed a high rate of apoptosis-induced DNA strand breaks in stable clones. In situ results were confirmed by FACScan analysis that showed an apoptotic rate of 44-47% compared with a 15% level in the control H460 cells. Analysis of cell cycle-phase distribution indicated a significant G(0)/G(1) arrest and the presence of a sub-G(1) peak in the stable clones. No significant changes in Bcl2, BclX, and Bax protein expression level were observed in the transfected clones as compared with the control H460 cells whereas a 2-fold increase in Bak protein levels was noticed. An increased level of p21(waf) protein paralleled by an up-regulation of p21(waf) transcripts also was found in Fhit-expressing clones compared with the H460 cell line. No differences in p53 levels were observed in the same cells, suggesting a p53-independent effect. These data suggest that the observed growth-inhibitory effect in FHIT-reexpressing cells could be related to apoptosis and cell cycle arrest and link the tumor-suppressor activity of FHIT to its proapoptotic function.

Acid Anhydride Hydrolases↗
PubMed1999

Cancer-specific chromosome alterations in the constitutive fragile region FRA3B.

We have sequenced 870 kilobases of the FHIT/FRA3B locus, from FHIT intron 3 to intron 7. The locus is AT rich (61.5%) and Alu poor (6. 2%), and it apparently does not harbor other genes. In a detailed analysis of the 308-kilobase region between FHIT exon 5 and the telomeric end of intron 3, a region known to encompass a human papillomavirus-16 integration site and two clusters of aphidicolin-induced chromosome 3p14.2 breakpoints, we have precisely mapped 10 deletion and translocation endpoints in cancer-derived cell lines relative to positions of specific repetitive elements, regions of high genome flexibility and aphidicolin-induced breakpoints. Conclusions are (i) that aphidicolin-induced breakpoint clusters fall close to high-flexibility sequences, suggesting that these sequences contribute directly to aphidicolin-induced fragility; (ii) that 9 of the 10 FHIT allelic deletions in cancer cell lines resulted in loss of exons, with 7 deletion endpoints near long interspersed nuclear elements or long terminal repeat elements; and (iii) that cancer-specific deletions encompass multiple high-flexibility genomic regions, suggesting that fragile breaks may occur at these regions, whereas repair of the breaks involves homologous pairing of flanking sequences with concomitant deletion of the damaged fragile sequence.

Acid Anhydride Hydrolases↗
PubMed1999

Role of TCL1 and ALL1 in human leukemias and development.

We have investigated the role of chromosomal translocations in the pathogenesis of human leukemias. The study of T-cell chronic lymphocytic leukemias and T-cell prolymphocytic leukemia has led to the identification of TCL1, a novel gene that is deregulated by translocations, t(14;14)(q11;q32), or inversions, inv(14)(q11;q32.1). Introduction of a human TCL1 gene juxtaposed to the Ick promoter into fertilized mouse eggs resulted in the development of transgenic mice that developed mature T-cell leukemias, indicating that TCL1 is a transforming oncogene. We have also investigated acute leukemias with abnormalities at chromosome 11q23. We have identified a gene, ALL1, that can fuse to many different genes in acute leukemias. We have also shown that ALL1 can fuse with ALL1 in acute myelogenous leukemia. We have proposed that the ALL1 fusion genes may act by a dominant negative mechanism.

Animals↗
PubMed1999

The FEZ1 gene at chromosome 8p22 encodes a leucine-zipper protein, and its expression is altered in multiple human tumors.

Alterations of human chromosome 8p occur frequently in many tumors. We identified a 1.5-Mb common region of allelic loss on 8p22 by allelotype analysis. cDNA selection allowed isolation of several genes, including FEZ1. The predicted Fez1 protein contained a leucine-zipper region with similarity to the DNA-binding domain of the cAMP-responsive activating-transcription factor 5. RNA blot analysis revealed that FEZ1 gene expression was undetectable in more than 60% of epithelial tumors. Mutations were found in primary esophageal cancers and in a prostate cancer cell line. Transcript analysis from several FEZ1-expressing tumors revealed truncated mRNAs, including a frameshift. Alteration and inactivation of the FEZ1 gene may play a role in various human tumors.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Positive regulation of the BRCA1 promoter.

Inherited mutations in the BRCA1 gene, presumably leading to loss of function, confer susceptibility to breast and ovarian neoplasms and are thought to be responsible for approximately 2.5-5% of all breast cancers. It has been suggested that alternative mechanisms, such as disruption of transcription, may also be involved in the suppression of BRCA1 gene expression/function in breast cancers. Therefore, we initiated studies on the BRCA1 transcriptional promoter. Utilizing systematic promoter deletions and transient transfection assays, a 36-base pair region was determined to be important for the positive regulation of BRCA1 transcription. Deletion of this positive regulatory region resulted in a significant loss of promoter activity. Utilizing DNA binding assays, proteins with specific affinities for the positive regulatory region were detected. Disruption of the DNA-protein complexes could affect normal BRCA1 transcription and may contribute to breast cancer susceptibility.

Breast Neoplasms↗
PubMed1999

Abnormalities at 14q32.1 in T cell malignancies involve two oncogenes.

The TCL1 oncogene on human chromosome 14q32.1 is involved in the development of T cell leukemia in humans. Its expression in these leukemias is activated by chromosomal translocations and inversions at 14q32.1. Here we report the isolation and characterization of a new member of the TCL1 gene family, TCL1b, located approximately 16 kb centromeric of TCL1. The 1.2-kb TCL1b cDNA encodes a 14-kDa protein of 128 aa and shows 60% similarity to Tcl1. Expression profiles of TCL1 and TCL1b genes are very similar: both genes are expressed at very low levels in normal bone marrow and peripheral lymphocytes but are activated in T cell leukemia by rearrangements of the 14q32.1 region. Thus, translocations and inversions at 14q32. 1 in T cell malignancies involve two oncogenes.

Amino Acid Sequence↗
PubMed1999

hMSH5: a human MutS homologue that forms a novel heterodimer with hMSH4 and is expressed during spermatogenesis.

MutS homologues have been identified in nearly all organisms examined to date. They play essential roles in maintaining mitotic genetic fidelity and meiotic segregation fidelity. MutS homologues appear to function as a molecular switch that signals genomic manipulation events. Here we describe the identification of the human homologue of the Saccharomyces cerevisiae MSH5, which is known to participate in meiotic segregation fidelity and crossing-over. The human MSH5 (hMSH5) was localized to chromosome 6p22-21 and appears to play a role in meiosis because expression is induced during spermatogenesis between the late primary spermatocytes and the elongated spermatid phase. hMSH5 interacts specifically with hMSH4, confirming the generality of functional heterodimeric interactions in the eukaryotic MutS homologue, which also includes hMSH2-hMSH3 and hMSH2-hMSH6.

Amino Acid Sequence↗
PubMed1999

ATM mutations in B-cell chronic lymphocytic leukemia.

Mutations in the ATM gene located on the long arm of chromosome 11 at 11q22-23 cause ataxia-telangiectasia, an autosomal recessive disorder that is associated with increased incidence of malignancy and, particularly, lymphoid tumors. A role for ATM in the development of sporadic T-cell chronic leukemias is supported by the finding of loss of heterozygosity at 11q22-23 and ATM mutations in leukemias carrying TCL-1 rearrangements. Approximately 14% of B-cell chronic lymphocytic leukemia (B-CLL), the most common adult leukemia, carry deletions of the long arm of chromosome 11 at 11q22-23. Loss of heterozygosity at 11q22-23 and, more recently, absence of ATM protein, have been associated with poor prognosis in B-CLL. To determine whether the ATM gene is altered in B-CLL, we have sequenced individual ATM exons in six B-CLL cases. We show that the ATM gene is mutated in a fraction of B-CLLs and that mutations can be present in the germ line of patients, suggesting that ATM heterozygotes may be predisposed to B-CLL.

Adult↗
PubMed1999

Advances in cancer cytogenetics.

As the end of the millenium approaches, recognition of the milestones achieved in the field of cancer cytogenetics is mandatory. With regard to cancer cytogenetics, the turning century can be divided in three main era: the pre-banding period that has posed important hypothesis and technical premises, the fruitful banding era that led to the discovery of the critical chromosomal rearrangements and cloning of cancer genes and the more recent revolutionizing era of molecular cytogenetics where technological advances permit a global visualization and high-level resolution of chromosomal alterations. J. Cell. Biochem. Suppls. 32/33:173-182, 1999.

Animals↗
PubMed1999

Duplicated regions of AF-4 intron 4 at t(4;11) translocation breakpoints.

BACKGROUND: AF-4 is a common partner gene of MLL. AF-4 breakpoints occur in introns, but most AF-4 introns are uncharacterized. METHODS AND RESULTS: We cloned AF-4 intron 4 and examined the frequency of breakpoints in this intron. The 5.8-kb intron is rich in repeat sequences and was the site of translocation in 3 of 17 leukemias with t(4;11). We cloned the der (11) and der (4) breakpoints and isolated the fusion transcripts in the cell line MV4-11 and in a de novo acute lymphoblastic leukemia (ALL). Both translocations joined MLL intron 6 and AF-4 intron 4. In MV4-11, 249 bases from AF-4 were present in both derivative chromosomes, indicating duplication. In the de novo ALL, duplication of 446 bases from MLL and AF-4 occurred. Reciprocal fusion transcripts were expressed. CONCLUSIONS: Intronic sequence of AF-4 is useful for molecular diagnosis of t(4;11). Duplicated intronic regions suggest staggered chromosomal breakage.

Adolescent↗
PubMed1999

Trithorax and ASH1 interact directly and associate with the trithorax group-responsive bxd region of the Ultrabithorax promoter.

Trithorax (TRX) and ASH1 belong to the trithorax group (trxG) of transcriptional activator proteins, which maintains homeotic gene expression during Drosophila development. TRX and ASH1 are localized on chromosomes and share several homologous domains with other chromatin-associated proteins, including a highly conserved SET domain and PHD fingers. Based on genetic interactions between trx and ash1 and our previous observation that association of the TRX protein with polytene chromosomes is ash1 dependent, we investigated the possibility of a physical linkage between the two proteins. We found that the endogenous TRX and ASH1 proteins coimmunoprecipitate from embryonic extracts and colocalize on salivary gland polytene chromosomes. Furthermore, we demonstrated that TRX and ASH1 bind in vivo to a relatively small (4 kb) bxd subregion of the homeotic gene Ultrabithorax (Ubx), which contains several trx response elements. Analysis of the effects of ash1 mutations on the activity of this regulatory region indicates that it also contains ash1 response element(s). This suggests that ASH1 and TRX act on Ubx in relatively close proximity to each other. Finally, TRX and ASH1 appear to interact directly through their conserved SET domains, based on binding assays in vitro and in yeast and on coimmunoprecipitation assays with embryo extracts. Collectively, these results suggest that TRX and ASH1 are components that interact either within trxG protein complexes or between complexes that act in close proximity on regulatory DNA to maintain Ubx transcription.

Amino Acid Sequence↗
PubMed1999

Exon structure and promoter identification of STIM1 (alias GOK), a human gene causing growth arrest of the human tumor cell lines G401 and RD.

The stromal interaction molecular 1 gene (STIM1) encodes a type I trans-membrane protein of unknown function, which induces growth arrest and degeneration of the human tumor cell lines G401 and RD but not HBL100 and CaLu-6, suggesting a role in the pathogenesis of rhabdomyosarcomas and rhabdoid tumors. Here, we describe the STIM1 genomic organization including the identification of the promoter region. The gene consists of 12 exons that span a region larger than 250 kb between the genes RRM1 and NUP98. Nucleotide sequences of all exon-intron boundaries were determined and oligonucleotide primers for the amplification of individual exons were designed. The promoter region was identified within a 1.8-kb SacI fragment at the 5' end of the gene. In vitro CpG methylation of the promoter region indicated that transcription can be downregulated by this mechanism. The genetic tools developed in the present work will help to determine whether pathogenetic mechanisms that associate STIM1 with tumorigenesis involve mutations in coding sequences and/or promoter, and whether methylation could determine STIM1 transcriptional down-regulation in tumor samples.

Cell Division↗
PubMed1999

Role of FHIT in human cancer.

Through investigation of hemizygous and homozygous deletions in common human cancers, including lung cancer, we have cloned and characterized a gene at chromosome region 3p14.2, FHIT, that is inactivated in epithelial tumors, particularly in tumors resulting from exposure to environmental carcinogens. In some tumors, particularly those associated with environmental carcinogens, alterations in the FHIT gene occur quite early in the development of cancer. In other cancers, Fhit inactivation seems to be a later event, possibly associated with progression to more aggressive neoplasias. Thus, detection of Fhit expression by immunohistochemistry in premalignant and malignant tissues may provide important diagnostic and prognostic information.

Acid Anhydride Hydrolases↗
PubMed1999

Loss of FHIT expression in acute lymphoblastic leukemia.

Loss of expression of the FHIT tumor suppressor gene is common in epithelial malignancies such as lung, kidney, esophageal, gastric, and cervical cancers. To assess the role of FHIT in acute leukemias, we examined 18 primary acute lymphoblastic leukemias (ALLs), 8 ALL-derived cell lines, 7 cell lines from other hematological malignancies, 14 lymphoblastoid cell lines, and 5 peripheral blood lymphocyte samples for expression of FHIT mRNA and protein by reverse transcription-PCR and Northern and Western blots. Fhit protein expression was detected in only 24% of primary ALLs and leukemia/lymphoma cell lines, but it was detected in all lymphoblastoid cell lines and peripheral blood lymphocyte samples. Interestingly, Fhit protein expression was lost in all T-cell ALLs but was lost in only half of the B-cell ALLs. Northern blotting of 7 normal lymphoblastoid cell lines and 13 of the neoplastic cell lines confirmed the results obtained by Western blotting regarding FHIT expression. The high frequency of loss of Fhit expression in ALLs suggests that inactivating alterations at the FHIT locus contribute to development of the leukemias.

Acid Anhydride Hydrolases↗
PubMed1999

Significance of FHIT expression in chronic myelogenous leukemia.

Loss or reduced expression of the fragile histidine triad (FHIT) gene, a tumor suppressor gene localized at chromosome 3p14.2, is common in several solid and hematological cancers and has been associated with tumor progression and worse prognosis. The role of the FHIT gene in the pathogenesis of chronic myelogenous leukemia (CML) or its progression from a chronic phase to the accelerated and blastic phases is not known. The aim of this study was to evaluate whether Fhit protein expression is altered in CML, and whether it plays any role in CML progression, disease responsiveness to therapy, or prognosis. A total of 195 patients with Philadelphia chromosome-positive CML were evaluated, including 129 patients in early chronic phase (time from diagnosis to study, 12 months or less), 30 patients in late chronic phase, and 36 patients in the accelerated and blastic phases. The levels of cellular Fhit protein expression were determined using Western blot analysis and solid-phase RIA and compared to the levels in 31 normal marrows. The median Fhit expression in normal marrows was assigned a value of 1, and the levels in CML samples were normalized to the median of the normal control. Fhit levels in CML samples were evaluated in relation to CML phase and patient characteristics and prognosis in the early chronic phase. The median Fhit value in CML samples was 0.89 (range, 0.34-2.62). Eight of the 195 (4%) CML samples showed Fhit levels <0.5 and lacked detectable Fhit protein by Western blot. There was no difference in the levels of Fhit expression by different CML phases. In early chronic phase, reduced Fhit expression tended to be associated with leukocytosis (P = 0.04) and lower platelet counts (P = 0.01), but not with poorer-risk groups. No differences in response to IFN-alpha therapy or in survival were observed by different Fhit levels. Lack of Fhit protein expression was detected in 4% of CML cases, and reduced expression occurred in a subpopulation of patients. However, reduced Fhit expression is not associated with progression, response to therapy, or prognosis in CML.

Acid Anhydride Hydrolases↗
PubMed1998

Loss of FHIT function in lung cancer and preinvasive bronchial lesions.

We previously cloned and characterized the tumor suppressor gene FHIT (fragile histidine triad) at chromosome 3p14.2 and found that this gene is altered by deletions in human tumors, including lung cancer. To assess the frequency and specificity of inactivation and its relevance in a clinical setting, we have produced antibodies against the Fhit protein and studied its expression in a series of non-small cell lung cancers and normal bronchial mucosa and a spectrum of preinvasive lesions by immunohistochemistry. The data indicate that the loss of Fhit protein is the most frequent alteration in non-small cell lung cancer (73%) and precancerous lesions (93%), is significantly higher in the tumors of smokers (75%) than in those of nonsmokers (39%; P < 0.0005), and is an independent and more frequent event than p53 overexpression in tumors and precancerous lesions (73 versus 46%). The percentage of cases lacking Fhit expression was higher in the squamous type compared to adenocarcinoma (87 versus 57%; P < 0.00001), whereas other histotypes (large cell, mucoepidermal) showed an intermediate value (69%). Loss of Fhit expression in a very high percentage of primary lung carcinomas and precancerous lesions supports the notion that FHIT alterations play an important role in the growth control of bronchial cells. FHIT inactivation is particularly important in squamous cell carcinomas that are often associated with precursor dysplastic lesions. The overall high frequency and precocity of Fhit loss in lung carcinogenesis and the development of the presently described immunohistochemical approach suggest a potential use of this gene in the early detection of lung cancer and in chemopreventive studies as an intermediate biomarker.

Acid Anhydride Hydrolases↗