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T Frebourg

Publications and source records attributed to T Frebourg.

At least 37 records · Page 2Linked to original sources
PubMed2001

Loss of MDM2 expression in human head and neck squamous cell carcinomas and clinical significance.

The transforming potential of the MDM2 oncogene has been attributed to the overproduction of the protein. In order to investigate regulation of MDM2 expression in head and neck squamous cell carcinomas, we analysed MDM2 gene amplification, and mRNA and protein expression in tumour specimens from 62 patients, in cell lines, and in normal epithelium adjacent to tumours or obtained from healthy patients. Additionally, TP53-induced MDM2-P2 transcription was evaluated and compared with TP53 status. MDM2 gene amplification and mRNA over-expression is infrequent, 7 and 9%, respectively. The predominant transcript codes for full-length MDM2 protein (90kD) and the level of alternatively spliced forms is not significant. We show that only 47% of tumours exhibit MDM2 immunostaining in more than one third of the neoplastic cells, and thus more than half of the tumours display no or low levels of MDM2 protein. In contrast, MDM2 protein is always detectable in basal and parabasal cells of morphologically normal epithelium outside the invasively growing tumour, as well as in a normal uvula sample. Similarly, the total amount of MDM2 transcripts analysed by reverse transcriptase-polymerase chain reaction is reduced in tumour samples compared to normal tissues, essentially due to a decrease in P2 transcript levels. The relationship between mutated p53 status and low levels of MDM2 found in cell lines is also observed to a certain extent in primary tumour samples. Overall, there is a high frequency of TP53 mutation and under-expression of MDM2 in the head and neck tumours. Moreover, a significant association of decreased MDM2 expression is observed with advanced tumour stage and 3 years survival.

Carcinoma, Squamous Cell↗
PubMed2001

TP63 gene mutation in ADULT syndrome.

TP63 gene mutations have recently been shown to be disease causing in EEC and SHFM. Two other overlapping syndromes with ectrodactyly as a major feature, have been mapped to chromosome 3q27 close by the TP63 locus, namely the LMS and ADULT syndromes. Here, we report on a missense TP63 gene mutation in an isolated ADULT syndrome case. This finding widens the spectrum of abnormalities to be ascribed to TP63 gene in human and emphasise on the variable roles of the different Tp63 isotypes.

Abnormalities, Multiple↗
PubMed2001

[Li-Fraumeni syndrome: update, new data and guidelines for clinical management].

The Li-Fraumeni syndrome (LFS) is an inherited form of cancer, affecting children and young adults, and characterized by a wide spectrum of tumors, including soft-tissue and bone sarcomas, brain tumours, adenocortical tumours and premenopausal breast cancers. In most of the families, LFS results from germline mutations of the tumor suppressor TP53 gene encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs. Recently, germline mutations of hCHK2 encoding a kinase, regulating cell cycle via Cdc25C and TP53, were identified in affected families. The LFS working group recommendations are the following: (i) positive testing (screening for a germline TP53 mutation in a patient with a tumor) can be offered both to children and adults in the context of genetic counseling associated to psychological support, to confirm the diagnosis of LFS on a molecular basis. This will allow to offer to the patient a regular clinical review in order to avoid a delay to the diagnosis of another tumor; (ii) the 3 indications for positive testing are: a proband with a tumor belonging to the narrow LFS spectrum and developed before age 36 and, at least, first- or second-degree relative with a LFS spectrum tumor, before age 46, or a patient with multiple primary tumors, 2 of which belonging to the narrow LFS spectrum, the first being developed before 36 or a child with an adenocortical tumour; (iii) presymptomatic testing must be restricted to adults; (iv) the young age of onset of the LFS tumors the prognosis of some tumors, the impossibility to ensure an efficient early detection and the risk for mutation carriers to develop multiple primary tumors justify that prenatal diagnosis might be considered in affected families.

Adult↗
PubMed2000

Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation.

The authors report a presenilin 1 (PSEN1) mutation (L113P) in a family with six cases of dementia. The patients had personality changes and behavioral disorders, whereas spatial orientation and praxis were preserved late in the course of the illness. Neuroimaging features were consistent with the diagnosis of frontotemporal dementia. The authors conclude that PSEN1 mutations can be associated with clinical features of frontotemporal dementia.

Adult↗
PubMed2000

Overexpression of Rab11 or constitutively active Rab11 does not affect sAPPalpha and Abeta secretions by wild-type and Swedish mutated betaAPP-expressing HEK293 cells.

Presenilins 1 and 2 are two homologous proteins which, when mutated, appear responsible for most of the early-onset familial forms of Alzheimer's disease. Among various functional aspects, presenilins appear to behave as chaperoning partners of a series of proteins including the beta-amyloid precursor protein. Recently, presenilins were shown to interact with Rab11, a GTPase involved in intracellular transport. This suggested that Rab11-presenilin interaction could influence the routing of betaAPP and thereby modulate its maturation. In this context, we examined whether overexpression of Rab11 or its constitutively active mutant Rab11Q70L could affect betaAPP maturation in human HEK293 cells. We show here that the overexpression of both Rab11-related proteins does not modify the recovery of secreted sAPPalpha or Abeta in HEK293 cells expressing wild-type betaAPP or betaAPP harboring the Swedish double mutation. These data indicate that Rab11 does not influence betaAPP processing in HEK293 cells. However, it does not preclude the possibility for Rab11 to modulate other presenilin-mediated functions in human cells.

Alzheimer Disease↗
PubMed2000

Detection of exon deletions and duplications of the mismatch repair genes in hereditary nonpolyposis colorectal cancer families using multiplex polymerase chain reaction of short fluorescent fragments.

Large genomic deletions within the mismatch repair MLH1 and MSH2 genes have been identified in families with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, and their detection represents a technical problem. To facilitate their detection, we developed a simple semiquantitative procedure based on the multiplex PCR of short fluorescent fragments. This method allowed us to confirm in HNPCC families three known deletions of MLH1 or MSH2 and to detect in 19 HNPCC families, in which analysis of mismatch repair genes using classical methods had revealed no alteration, a deletion of exon 5 and a duplication of MSH2 involving exons 9 and 10. The presence of such duplications, the frequency of which is probably underestimated, must be considered in HNPCC families in which conventional screening methods have failed to detect mutations.

Adaptor Proteins, Signal Transducing↗
PubMed2000

APOE promoter polymorphisms do not confer independent risk for Alzheimer's disease in a French population.

The apolipoprotein E (APOE, gene; apoE, protein) isoforms are associated with differential risk of Alzheimer's disease (AD). An additional involvement of APOE promoter polymorphisms in AD risk has recently been suggested by several studies. Indeed, three polymorphisms of the APOE regulatory region (-219 G/T, -427 C/T and -491 A/T) have been found associated with AD even after adjustment on the apoE status. We analysed these three promoter region polymorphisms in a large French case-control study (388 AD cases and 386 controls). We found that the -427 T and -491 A alleles were associated with an increased risk of developing AD, but not the -219 G/T alleles. However, a strong linkage disequilibrium was observed between the alleles of these promoter region polymorphisms and the APOE coding region alleles. We therefore retested association after adjustment on apoE status and found that the sole association which remained significant was the association with the -427 T allele. The alpha level was equal to 0.03 (0.09 after Bonferroni correction for multiple comparisons). Analysis of promoter haplotypes also yielded non-significant results. Thus our study does not reinforce the hypothesis of an independent involvement of the APOE promoter region polymorphisms in AD risk.

Adult↗
PubMed2000

High frequency in esophageal cancers of p53 alterations inactivating the regulation of genes involved in cell cycle and apoptosis.

Somatic mutations of the tumor suppressor gene p53 have been frequently detected in esophagal cancers, but their biological significance remains to be established. The tumor suppressor activity of p53 results in part from its ability to transactivate genes involved in the cell cycle and apoptosis, such as p21, bax and PIG3, and some p53 mutations may have a differential effect on the transactivation of these target genes. We developed yeast strains in which the activation by wild-type p53 of reporter plasmids containing p53 binding sites present within these target genes induces a change in the color of the colonies (red/white). Using these strains, we analyzed 56 esophageal cancers from patients residing in Normandy, France, a high incidence geographic area. Forty-seven tumors (84%), scored as mutant with the p21, bax and PIG3 reporter strains and in most of the cases (76%), the percentage of red colonies suggested that both p53 alleles were inactivated. Sequencing analysis allowed the identification of a p53 mutation in each positive sample, and the spectrum of mutations was in agreement with the etiological role of tobacco and alcohol. These results confirm the high frequency of biallelic p53 mutations in esophageal carcinoma and strongly suggest that their biological consequence is the complete alteration of the transactivation of genes involved in the cell cycle and apoptosis, which indicates that p53 alteration is a key event in esophagus carcinogenesis.

Apoptosis↗
PubMed1999

Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum.

To determine the prevalence of early-onset Alzheimer disease (EOAD) and of autosomal dominant forms of EOAD (ADEOAD), we performed a population-based study in the city of Rouen (426,710 residents). EOAD was defined as onset of disease at age <61 years, and ADEOAD was defined as the occurrence of at least three EOAD cases in three generations. Using these stringent criteria, we calculated that the EOAD and ADEOAD prevalences per 100,000 persons at risk were 41.2 and 5.3, respectively. We then performed a mutational analysis of the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) in 34 families with ADEOAD ascertained in France. In 19 (56%) of these families, we identified 16 distinct PSEN1 missense mutations, including 4 (Thr147Ile, Trp165Cys, Leu173Trp, and Ser390Ile) not reported elsewhere. APP mutations, including a novel mutation located at codon 715, were identified in 5 (15%) of the families. In the 10 remaining ADEOAD families and in 9 additional autosomal dominant Alzheimer disease families that did not fulfill the strict criteria for ADEOAD, no PSEN1, PSEN2, or APP mutation was identified. These results show that (1) PSEN1 and APP mutations account for 71% of ADEOAD families and (2) nonpenetrance at age <61 years is probably infrequent for PSEN1 or APP mutations.

Adult↗
PubMed1999

Presenilins interact with Rab11, a small GTPase involved in the regulation of vesicular transport.

Presenilin 1 (PS1) mutations account for the majority of early-onset dominant cases of familial Alzheimer's disease. Presenilins (PSs) are located in many intra-cellular compartments such as the endoplasmic reticulum, Golgi apparatus, nuclear region and vesicular structures. These proteins include from seven to nine putative transmembrane domains, with the N- and C-terminal ends and a large hydrophilic loop orientated towards the cytoplasm. We report an interaction between the human PS1 or PS2 hydrophilic loop and Rab11, a small GTPase belonging to the Ras-related superfamily. Interaction domains were mapped to codons 374-400 for PS1 and to codons 106-179 for Rab11, a region including the fourth GTP-binding domain. Considering the implication of Rab proteins in vesicular transport pathways, the PS-Rab11 inter-action suggests that PSs might be involved in amyloid precursor protein vesicular routing.

Amino Acid Sequence↗
PubMed1999

p53 mutations in bladder tumors inactivate the transactivation of the p21 and Bax genes, and have a predictive value for the clinical outcome after bacillus Calmette-Guerin therapy.

PURPOSE: We analyze the relationship among p53 mutations, p21 and Bax activation as well as their clinical implication in clinical response to intravesical bacillus Calmette-Guerin (BCG) therapy in high grade bladder tumors. MATERIALS AND METHODS: We analyzed a prospective series of 60 superficial bladder tumors using functional assays in yeast which test the transcriptional competence of p53 and can be used to identify p21 and Bax status. BCG instillations were given after initial tumor resection to 26 patients with a high risk of bladder invasive disease (pT1G3 tumors in 24 and carcinoma in situ in 2). RESULTS: No p53 alteration was detected in cases of pTa tumors. In contrast, p53 mutations were detected in 16 of 24 patients (66%) with pT1 G3 tumors and in 2 with primary carcinoma in situ. These 18 mutant samples scored also mutant for transactivation of p21 and Bax reporter strain. In 26 bladder tumors treated with BCG instillations there was a statistical difference (p = 0.0075) in the response to BCG therapy between 18 tumors with and 8 without alterations using functional assays in yeast. CONCLUSIONS: The p53 mutations, using functional assay in yeast, inactivate the transcription of p21 and Bax genes, and based on these preliminary results could have a useful predictive value for BCG therapy response in bladder cancer.

Adjuvants, Immunologic↗
PubMed1999

Selective detection of inactivating mutations of the tumor suppressor gene p53 in bladder tumors.

OBJECTIVE: Mutations in the p53 gene are implicated in the pathogenesis of half of all human tumors. In bladder tumors they are usually detected by immunohistochemistry. The assumption underlying protein analysis is that high level p53 expression is a consequence of mutations, but numerous exceptions have been reported. We describe the detection of p53 mutations in bladder cancer using a functional assay in yeast. MATERIALS AND METHODS: The prospective study consisted of 60 consecutive patients with bladder tumors (7 pT0, 2 CIS, 23 pTa, 24 pT1 and 4 pT2). High grade 3 was observed in primary carcinoma in situ, in 75% of pT1 tumors and in all pT2 tumors. The p53 mRNA extracted from endoscopic resection tissue was reverse transcribed and PCR-amplified. The transcriptional competence of the p53 cDNA was then tested in a yeast reporter strain. A simple functional assay was developed for p53 mutation in which human p53 is expressed in Saccharomyces cerevisiae which activates transcription of the ADE2 gene. Colonies containing wild type p53 are white and colonies containing mutant p53 are red. RESULTS: As this assay evaluates the critical biological function of p53, it can distinguish inactivating mutations from functionally silent mutations. In pTo and pTa bladder tumors, no p53 mutations were detected. In contrast, the functional assay permitted us to detect p53 mutations in 66% of patients with stage T1 tumors (72% of case of high grade 3) and in all cases with primary carcinoma in situ and in 4 cases of stage T2 tumors. CONCLUSION: This preliminary study demonstrates that this functional assay method is a simple and efficient procedure to detect p53 mutations in bladder cancers and suggests that p53 mutations seem to be associated with invasive bladder tumors.

Chromosomes, Artificial, Yeast↗
PubMed1998

Structural and functional analysis of the 5'-transcription control region for the human alpha2-HS glycoprotein gene.

The human alpha2-HS glycoprotein (A2HS) and rat phosphoprotein of Mr 63000 (pp63) are homologous plasma proteins and members of the fetuin superfamily. A2HS is involved in important functions such as inhibition of the tyrosine kinase activity of the insulin receptor, regulation of calcium metabolism and osteogenesis as well as protease inhibitory activity. We report an analysis of the 5' transcription control region (4 kb) of the A2HS gene. Its most proximal 300 nt display a very potent transcriptional activity. The latter is likely accounted for by C/EBP and NF1 binding sites that are conserved from the human A2HS gene to the rat pp63 gene. In contrast, these human and rat genes appear to largely diverge beyond their proximal promoter.

Base Sequence↗
PubMed1998

Identification of human p53 mutations with differential effects on the bax and p21 promoters using functional assays in yeast.

Recent studies have suggested that a rare class of p53 mutants found in tumours has a subtle transcriptional defect affecting bax induction but not p21 induction. We have therefore developed simple functional assays in yeast which can be used to identify these mutants. Analysis of 51 different mutations observed in human tumours showed that all mutants tested scored as mutant with the bax reporter strain but nine scored as wild-type with the p21 reporter strain. These results, which can be explained by the lower affinity of the p53 protein for the bax site, may suggest that p21 is not the key target of p53 mutations in tumours. Since p21 status has recently been shown to modulate the chemotherapeutic and radiotherapeutic sensitivities of cancerous cells, the functional assays described here may have important clinical implications.

Base Sequence↗
PubMed1998

No association of apolipoprotein epsilon 4 allele with schizophrenia even in cognitively impaired patients.

Given the strong association of the apolipoprotein E (apoE) allele epsilon 4 (epsilon 4) with Alzheimer's disease or cognitive decline in elderly, we tested whether cognitive performance in schizophrenic subjects is associated with an increase in the frequency of the ApoE epsilon 4 allele. Our data indicate that in our sample: (1) there is no association between schizophrenia and the ApoE epsilon 4 allele; and (2) the ApoE epsilon 4 allele is not of major importance with regard to the cognitive decline observed in schizophrenia.

Adult↗
PubMed1998

Apolipoprotein E epsilon4 allele and familial aggregation of Alzheimer disease.

OBJECTIVE: To investigate the relationship among risk for Alzheimer disease (AD), familial aggregation of AD, and the apolipoprotein E (apoE) epsilon4 allele in first-degree relatives of probands with AD and known apoE genotype. PATIENTS: Two hundred ninety subjects fulfilling the criteria of the National Institute of Neurological Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association for probable AD were ascertained from March 1, 1992, to December 31, 1996, through consecutive admissions in several university hospitals. DESIGN AND METHODS: Family data were collected on 1176 first-degree relatives (parents and siblings), aged 40 to 90 years. Most living relatives underwent a clinical examination, whereas we relied on family history for clinical data for deceased or unavailable relatives. First, we conducted standard survival analyses to estimate cumulative lifetime risk (LTR) for AD among relatives and to investigate for sex and apoE genotype effects on LTR. Then, we assessed to what extent clustering of secondary AD could be explained by the apoE epsilon4 allele by deriving the expected proportions of relatives with 0, 1, or 2 apoE epsilon4 alleles conditionally on the proband's genotype. RESULTS: Cumulative LTR for AD among first-degree relatives increased significantly with the number of epsilon4 alleles present in the proband. By 90 years of age, LTRs in relatives of probands with epsilon3/epsilon3, epsilon3/epsilon4, and epsilon4/epsilon4 genotypes were 29.2%, 46.1%, and 61.4%, respectively. Significant sex-by-apoE genotype interaction effects on LTR were observed. Women had about a 2-fold higher risk for AD than men among relatives of epsilon4 carriers but not among relatives of non-epsilon4 carriers. The predicted proportion of epsilon4 carriers in relatives of probands with epsilon3/epsilon3 genotype remains about 50% lower than the corresponding LTR for AD, indicating that familial clustering of AD is largely due to other factors than the apoE epsilon4 allele. Although aggregation of AD in families of probands with the epsilon4 allele is more prominent, we estimated that AD would not develop in about 30% of female and up to 60% of male relatives carrying at least 1 epsilon4 allele, even by 90 years of age. CONCLUSION: Our results support the hypothesis that the apoE epsilon4 allele enhances AD susceptibility, but putative factors enhancing risk for AD remain to be found.

Adult↗
PubMed1998

Functional analysis of the p53 protein in AIDS-related non-Hodgkin's lymphomas and polymorphic lymphoproliferations.

Alteration of the tumour suppressor gene p53 is frequent in AIDS-related non-Hodgkin's lymphomas (AIDS-NHL), particularly in Burkitt's or Burkitt's-like lymphomas (BL/BLL). Since mechanisms of inactivation other than mutations have been advanced, the transcriptional activity of the p53 protein was studied in a functional assay in yeast in a series of AIDS-NHL lesions and compared with their morphology, immunohistochemistry (IHC) and single-strand conformation polymorphism (SSCP) analysis detection of other p53 abnormalities, Epstein-Barr virus (EBV) status, MDM-2 oncoprotein expression and c-MYC rearrangement. Polymorphic lymphoproliferations (PL), identified as precursors of NHL in HIV-patients, were also analysed in attempt to detect p53 modifications related to clonal progression. The functional assay detected p53 mutants in 40% (12/ 30) of the tumours: 50% (6/12) of BL/BLL, 40% (4/10) of diffuse large cell lymphomas (DLCL) and 25% (2/8) of PL. An oligoclonal or monoclonal population was identified in the two PL cases with mutant p53. An accumulation of the p53 protein was detected by IHC in 26% (8/30) of the tumours (five BL/BLL and three DLCL) and was associated with positive functional assay. In the 20 lesions tested by both of the screening methods for mutations, a p53 mutant pattern was detected in 55% of cases (11/20) and in 25% of cases (5/ 20) respectively with the functional assay and SSCP analysis of exons 5-8. There was no inverse correlation between the detection of EBV genome and the presence of p53 mutations and no overexpression of MDM-2 protein for the whole series. In conclusion, the functional assay was more sensitive than IHC and SSCP for the detection of p53 mutations in tumour samples. The mutations identified in AIDS-NHL lesions inactivate the p53 protein and in PL they could represent a selection of an aggressive clone.

Cell Division↗