PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis.
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The level of phosphorylation within cells is tightly regulated by the concerted action of protein kinases and protein phosphatases [Hunter, T. (1995) Cell 80, 225-236]. Disregulation in the activity of either of these players can lead to cellular transformation. Many protein tyrosine kinases are proto-oncogenes and it has been postulated that some protein phosphatases may act as tumor suppressors. Herein we will review the recent findings addressing the roles the candidate tumor suppressor PTEN/MMAC1/TEP1 (PTEN, phosphatase and tensin homologue deleted from chromosome 10; MMAC 1, mutated in multiple advanced cancers 1; TEP1, TGF beta regulated and epithelial cell enriched phosphatase 1) plays in signal transduction and tumorigenesis. PTEN is a dual specificity protein phosphatase (towards phospho-Ser/Thr and phospho-Tyr) and, unexpectedly, also has a phosphoinositide 3-phosphatase activity. PTEN plays an important role in the modulation of the 1-phosphatidylinositol 3-kinase (PtdIns 3-kinase) pathway, by catalyzing the degradation of the PtdIns(3,4,5)P3 generated by PtdIns 3-kinase; this inhibits the downstream functions mediated by the PtdIns 3-kinase pathway, such as activation of protein kinase B (PKB, also known as Akt), cell survival and cell proliferation. Furthermore, PTEN modulates cell migration and invasion by negatively regulating the signals generated at the focal adhesions, through the direct dephosphorylation and inhibition of focal adhesion kinase (FAK). Growth factor receptor signaling is also negatively regulated by PTEN, through the inhibition of the adaptor protein Shc. While some of the functions of PTEN have been elucidated, it is clear that there is much more to discover about the roles of this unique protein. (+info)
Genetic polymorphism of the mannose-binding protein gene in children with sickle cell disease: identification of three new variant alleles and relationship to infections.
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Mannose-binding protein (MBP) is a serum lectin that participates in the innate immune response. MBP deficiency may constitute a risk factor in the development of infections. Three MBP structural variants have been identified with a dominant effect on MBP serum concentration. Similarly, polymorphisms in the promoter of the corresponding gene (HSMBP1B) have been related to variations of MBP concentration in serum. Children with sickle cell disease (SCD) have an increased susceptibility to infections with encapsulated organisms resulting in meningitis, septicaemia, and osteomyelitis. We have investigated the HSMBP1B genotype in 242 children with SCD living in Paris. Apart from the known variant alleles, we identified three novel ones and report their distribution in our sample population. In addition, we found rather unexpectedly an increased frequency of the variant alleles in patients who had not suffered severe infections. (+info)
Overexpression of the Tpl-2/Cot oncogene in human breast cancer.
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Tpl-2/Cot proto-oncogene encodes a serine threonine kinase and was initially cloned as a provirus insertion site in MoMuLV-induced T cell lymphomas in rats. Tpl-2 locus was also shown to be affected by provirus insertion in MMTV-induced mammary carcinomas in mice. The involvement of Tpl-2 in 35 human breast paired tumour specimens versus their corresponding adjacent normal tissue was evaluated. Tpl-2 was found overexpressed in 14 of the 35 breast tumours tested using a semi-quantitative RT - PCR method. Gene amplification was detected in eight out of the 14 specimens overexpressing Tpl-2, suggesting the increased number of copies of Tpl-2 gene as a possible mechanism for Tpl-2 overexpression. Significant association was found between the overexpression of Tpl-2 and stage I of the tumours, indicating that this molecular alteration may be an early event in the development of the disease. Furthermore, overexpression of Tpl-2 was associated with positive progesterone receptor status of the samples. This is the first report on the Tpl-2 oncogene linked to human breast tumours suggesting that it may be a key molecule for the study of human breast cancer. (+info)
Characterization and expression of sema4g, a novel member of the semaphorin gene family.
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Semaphorins constitute a large and growing gene family, several members of which are axon guidance molecules. We report the characterization of sema4g, a novel class IV member of the semaphorin gene family, located on mouse chromosome 19. sema4g is expressed early in development in the brain, spinal cord, and several sensory organs as well as specific populations of projection neurons, compatible with the well-established function of semaphorins as axon guidance molecules. (+info)
Identification of a human histone acetyltransferase related to monocytic leukemia zinc finger protein.
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We describe here the identification and functional characterization of a novel human histone acetyltransferase, termed MORF (monocytic leukemia zinc finger protein-related factor). MORF is a 1781-residue protein displaying significant sequence similarity to MOZ (monocytic leukemia zinc finger protein). MORF is ubiquitously expressed in adult human tissues, and its gene is located at human chromosome band 10q22. MORF has intrinsic histone acetyltransferase activity. In addition to its histone acetyltransferase domain, MORF possesses a strong transcriptional repression domain at its N terminus and a highly potent activation domain at its C terminus. Therefore, MORF is a novel histone acetyltransferase that contains multiple functional domains and may be involved in both positive and negative regulation of transcription. (+info)
Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast.
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Germline mutations in PTEN, encoding a dual-specificity phosphatase on 10q23.3, cause Cowden syndrome (CS), which is characterized by a high risk of breast and thyroid cancers. Loss of heterozygosity of 10q22-24 markers and somatic PTEN mutations have been found to a greater or lesser extent in a variety of sporadic component and noncomponent cancers of CS. Among several series of sporadic breast carcinomas, the frequency of loss of flanking markers around PTEN is approximately 30 to 40%, and the somatic intragenic PTEN mutation frequency is <5%. In this study, we analyzed PTEN expression in 33 sporadic primary breast carcinoma samples using immunohistochemistry and correlated this to structural studies at the molecular level. Normal mammary tissue had a distinctive pattern of expression: myoepithelial cells uniformly showed strong PTEN expression. The PTEN protein level in mammary epithelial cells was variable. Ductal hyperplasia with and without atypia exhibited higher PTEN protein levels than normal mammary epithelial cells. Among the 33 carcinoma samples, 5 (15%) were immunohistochemically PTEN-negative; 6 (18%) had reduced staining, and the rest were PTEN-positive. In the PTEN-positive tumors as well as in normal epithelium, the protein was localized in the cytoplasm and in the nucleus (or nuclear membrane). Among the immunostain negative group, all had hemizygous PTEN deletion but no structural alteration of the remaining allele. Thus, in these cases, an epigenetic phenomenon such as hypermethylation, -ecreased protein synthesis or increased protein degradation may be involved. In the cases with reduced staining, 5 of 6 had hemizygous PTEN deletion and 1 did not have any structural abnormality. Finally, clinicopathological features were analyzed against PTEN protein expression. Three of the 5 PTEN immunostain-negative carcinomas were also both estrogen and progesterone receptor-negative, whereas only 5 of 22 of the PTEN-positive group were double receptor-negative. The significance of this last observation requires further study. (+info)
An autosomal dominant thrombocytopenia gene maps to chromosomal region 10p.
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The increasing number of diagnosed cases of inherited thrombocytopenias, owing to the routine practice of including platelet counts in blood tests, suggests that this condition is not so rare as expected. In the majority of cases, the molecular basis of the disease is unknown, although the defect is likely to affect thrombocytopoiesis and regulation of the normal platelet count. Here we report a genomewide search in a large Italian family affected by autosomal dominant thrombocytopenia. Patients showed a moderate thrombocytopenia with minimal symptoms characterized by normocellular bone marrow, normal medium platelet volume, and positive aggregation tests. Microsatellite analysis demonstrated that the disease locus (THC2) is linked to chromosome 10p11.1-12, within a candidate region of 6 cM between markers D10S586 and D19S1639. A maximum LOD score of 8.12 at recombination fraction.00 was obtained with the microsatellite D10S588. These data localized the first locus of an autosomal dominant thrombocytopenia, and the subsequent identification of the gene will provide new insight into the basic mechanism of megakaryocytopoiesis disorders. (+info)
Genome scan for blood pressure loci in mice.
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Hypertension is a complex trait of unknown cause in humans. Mice of the inbred strain BPH/2 serve as a rodent model of human hypertension and display elevated blood pressure compared with the hypotensive strain BPL/1. An F2 intercross of BPH/2 and BPL/1 and 2 backcrosses of BPL/1 with Mus spretus were used to perform interval linkage mapping for systolic blood pressure in a genome scan. Significant linkage was observed in the F2s on chromosome 10 (logarithm of the odds score [LOD]=4.9) and on chromosome 13 in the M spretus backcross (LOD=3.3), with additional suggestive LODs on chromosomes 2, 6, 8, and 18. In addition, several suggestive linkages were observed for phenotypes associated with human hypertension. Our study is the first reported genome-wide linkage scan for blood pressure genes in the mouse. (+info)