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p63 and E-cadherin Expression in Canine Oral Squamous Cell Carcinoma

Mestrinho, L. A.; Pissarra, H.; Faísca, P. B.; Bragança, M.; Peleteiro, M. C.; Niza, M. M.
Fonte: Veterinary Pathology Publicador: Veterinary Pathology
Tipo: Artigo de Revista Científica
ENG
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The expression of p63 and E-cadherin was studied in 22 oral squamous cell carcinomas in the dog according to immunohistochemical techniques. The association between these markers and clinicopathologic parameters was assessed. All tumor cells studied showed enhanced p63 expression. Regarding E-cadherin expression, 17 of 22 cases (77.3%) showed decreased immunoreactivity, and in 13 of 22 cases (59.1%), its expression was cytoplasmic. Neither p63 nor E-cadherin expression patterns were associated with tumor size, bone invasion, or lymph node metastasis. p63 score was related to proliferating cell nuclear antigen proliferative index (P = .020). A statistically significant correlation between the expression patterns of these 2 markers was noted (P = .026). Furthermore, they were related with tumor grade. An atypical p63 labeling and a cytoplasmic E-cadherin staining were statistically related with a higher tumor grade (P = .022 and P = .017, respectively). These findings suggest that changes in p63 and E-cadherin expression are frequent events in oral squamous cell carcinoma in dogs.

Expression Profile of p63 in 127 Patients with Laryngeal Squamous Cell Carcinoma

BORBA, M.; CERNEA, C.; DIAS, F.; FARIA, P.; BACCHI, C.; BRANDAO, L.; COSTA, A.
Fonte: KARGER Publicador: KARGER
Tipo: Artigo de Revista Científica
ENG
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Objectives: To evaluate p63 expression in laryngeal squamous cell carcinoma and its prognostic significance. Methods: p63 expression was examined by immunohistochemistry and scored in 127 patients with laryngeal squamous cell carcinomas. Results: Sixty-two cases had scored 3, sixty had scored 2, four had scored 1 and one case did not show any expression (48.8, 47.2, 3.1 and 0.8%, respectively). Overall survival was 73.9% at 24 months and 59.5% at 60 months. The disease-free survival was 77.2 and 75.1%, and the disease-specific survival was 79 and 67% at 24 and 60 months, respectively. Uni- and multivariate analysis identified that decreased immunoexpression of protein p63 was a statistically significant factor for the risk of recurrence and death by cancer. Conclusions: p63 expression was highly prevalent in laryngeal squamous cell carcinomas, and its underexpression was correlated with a worse prognosis. Copyright (C) 2010 S. Karger AG, Basel

Impacto prognóstico da expressão imunohistoquímica do p53 e p63 e o papel do HPV no carcinoma epidermóide oral; Prognostic impact of p53 and p63 immunoexpression and the HPV role in oral squamous cell carcinoma.

Oliveira, Lucinei Roberto de
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 30/05/2008 PT
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O Brasil está entre os países com os maiores índices de carcinoma epidermóide oral (CEO). O gene p63 é um análogo do supressor tumoral p53 e a influência da expressão de ambos no prognóstico do CEO ainda necessita ser melhor investigada. O envolvimento do papilomavírus humano (HPV) no CEO é outro fator ainda não elucidado. Nosso estudo objetivou avaliar os pacientes com CEO no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, assim como também investigar a relação entre a presença do HPV e a imunoexpressão das proteínas p53 e p63 com alguns parâmetros relevantes ao prognóstico deste tumor. Os seguintes dados foram obtidos dos prontuários médicos de 424 pacientes: idade, gênero, localização e tamanho da lesão primária, história pregressa, consumo de tabaco e álcool, exposição actínica, traumatismo por prótese, recidivas, metástases, diferenciação tumoral, tratamento, sobrevida e óbitos. Cento e vinte e seis pacientes foram selecionados para o estudo da sobrevida, 106 para o estudo imunohistoquímico, 45 para a investigação IHQ com amostras pareadas (AP) e 87 para a reação em cadeia da polimerase para detecção do HPV e análise multivariada. Os tumores tiveram predominância em pacientes masculinos na 6ª década de vida...

Análise da expressão imunoistoquímica da proteína p63 e de seu valor prognóstico em carcinomas epidermóides da laringe; Analysis of p63 protein immunohistochemical expression and Its prognostic value in laryngeal squamous cells carcinomas

Borba, Marcus Antônio de Mello
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 02/07/2008 PT
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INTRODUÇÃO: Alterações genéticas múltiplas são comuns durante a carcinogênese e, nesse panorama, o gene supressor tumoral TP53 é um dos mais associados à transformação maligna. Recentemente, dois genes similares ao TP53, foram identificados, o TP73 e o TP63. O TP63 situa-se no cromossomo 3q e tem papel comprovado no desenvolvimento epidérmico, sendo detectado em vários tecidos humanos. Inúmeros trabalhos relacionaram a expressão da proteína p63 com carcinomas do trato aerodigestivo superior. OBJETIVOS: O presente estudo objetivou avaliar a expressão Imunoistoquímica da proteína p63 e seu valor prognóstico nos carcinomas epidermóides da laringe. CASUÍSTICA E MÉTODOS: Foram estudados retrospectivamente 127 pacientes submetidos a laringectomia total no Instituto Nacional de Câncer, Rio de Janeiro, entre 1998 e 2000. Houve 111 doentes masculinos e 16 femininos, 69 brancos e 58 não-brancos, com idade entre 36 a 93 anos, média de 59 e mediana de 58 anos. Dezenove tumores eram glóticos, 16 supraglóticos e 92 acometiam mais de um local, correspondendo a 15%, 13% e 72% respectivamente. Quanto ao estadiamento clínico, dois casos eram do estádio I (1,6%), 21 do II (16,5%), 82 do III (64,6%) e 22 do IV (17,3%). Noventa e seis pacientes (75...

Proliferation and apoptotic rates and increased frequency of p63-positive cells in the prostate acinar epithelium of alloxan-induced diabetic rats

Arcolino, Fanny Oliveira; Ribeiro, Daniele Lisboa; Gobbo, Marina Guimaraes; Taboga, Sebastiao Roberto; Goes, Rejane Maira
Fonte: Wiley-Blackwell Publishing, Inc Publicador: Wiley-Blackwell Publishing, Inc
Tipo: Artigo de Revista Científica Formato: 144-154
ENG
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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Processo FAPESP: 06/07008-3; P>The effects of experimental type 1 diabetes were investigated in the acinar epithelium of rat ventral prostate, focusing on the rates of cell proliferation and the frequency of apoptosis and p63-positive cells. Type 1 diabetes was induced in adult male Wistar rats by a single alloxan administration (42 mg/kg b.w.) and its effects were analysed for 1 week and 3 months after the establishment of the disease. A group of diabetic rats was treated daily with 5 IU of insulin during 1 week after diabetes had been diagnosed. Immunocytochemical methods for the localization of cell proliferation antigen (PCNA), androgen receptor (AR) and p63 protein were carried out, and apoptotic cells were identified by TUNEL essay. In diabetic rats, testosterone levels reduced drastically after 1 week and in a lower degree after 3 months. In short-term diabetic rats, cell proliferation decreased, and in medium-term, epithelial apoptotic rates increased. In both periods after the onset of diabetes, the frequency of p63-positive cells doubled. Insulin treatment was effective in preventing testosterone decrease...

Distribution of p63, a novel myoepithelial marker, in fine-needle aspiration biopsies of the breast : an analysis of 82 samples

Reis Filho, Jorge S.; Milanezi, Fernanda; Amendoeira, Isabel; Albergaria, André; Schmitt, Fernando C.
Fonte: Wiley Publicador: Wiley
Tipo: Artigo de Revista Científica
Publicado em //2003 ENG
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BACKGROUND. The presence of myoepithelial cells (MECs) in fine-needle aspiration biopsies (FNAB) of the breast constitute an important criterion used to diagnose benign breast lesions. However, MECs sometimes have a distorted cytomorphology, and most of the previously evaluated myoepithelial markers do not have satisfactory sensitivity and specificity. p63, a recently characterized p53 homolog, is a nuclear transcription factor that is expressed in basal cells of multilayered epithelia and myoepithelial cells of the breast. The authors analyzed the immunocytochemical distribution of p63 in a series of 82 breast FNABs (30 benign lesions and 52 malignant breast lesions). METHODS. Eighty-two archival, Papanicolaou-stained smears of breast lesions were retrieved from the files of the authors’ institutions. Immunocytochemistry was performed according to the streptavidin-biotin-peroxidase complex technique using the antibody 4A4 (against all p63 isoforms). Two pathologists evaluated the distribution of p63 positive cells. Only nuclear reactivity was considered specific. RESULTS. In benign lesions, p63 decorated the nuclei of MECs in all samples. p63 also stained naked nuclei in fibroadenomas. In malignant lesions, p63 was positive in MECs overlying malignant cell clusters in all 8 samples of ductal carcinoma in situ (DCIS)...

Naked nuclei revisited : p63 immunoexpression

Reis Filho, Jorge S.; Albergaria, André; Milanezi, Fernanda; Amendoeira, Isabel; Schmitt, Fernando C.
Fonte: Wiley Publicador: Wiley
Tipo: Artigo de Revista Científica
Publicado em //2002 ENG
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The presence of naked nuclei (NN) in cytological preparations of fibroadenomas is a well-known finding. Regardless of their importance on the differential diagnosis of fibroadenoma and other benign lesions of the breast, the origin of NN remains elusive. Despite previous efforts to characterize them, the lack of a reliable nuclear marker for myoepithelial cells impaired definitive conclusions. We performed a systematic evaluation of p63 expression in cytological and histological preparations of 10 fibroadenoma specimens. We observed that in histological sections, p63 was restricted to the nuclei of myoepithelial/basal cells in lobules and ducts of normal breast. In fibroadenomas, p63 decorated the nuclei of myoepithelial cells in the periphery of epithelial duct-like formations and slit-like formations. No p63 immunoreactivity was observed in stromal or epithelial cells. In cytological samples, almost all NN and cells surrounding epithelial cell clusters were stained; no stromal cell admixed with fibrillary matrix or epithelial cell was stained with p63. Based on our findings, we strongly suggest that most, if not all, NN are myoepithelial in origin.; Fundação para a Ciência e a Tecnologia (FCT) - grant SFRH/BD/5386/2001.

p63 expression in normal skin and usual cutaneous carcinomas

Reis Filho, Jorge S.; Torlo, Beatriz; Albergaria, André; Schmitt, Fernando C.
Fonte: Blackwell Publicador: Blackwell
Tipo: Artigo de Revista Científica
Publicado em //2002 ENG
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Background: p63 is a p53 homologue that is mapped to chromosome 3q27. This gene encodes six different isoforms, which have either transactivating or dominant negative effects on p53-reporter genes. It has been described that in contrast to p53, p63 seems not to be associated with tumor predisposition, as neither p63 knockout mouse models nor germline p63 mutations are related to an increased risk of tumorigenesis. It has been demonstrated that p63 is a reliable keratinocyte stem cell marker and that it is involved in the maintenance of the stem cell population. Scant data on p63 expression in normal skin, basal cell carcinomas (BCCs), keratoacanthomas and squamous cell carcinomas (SCCs) have been reported. We herein evaluated p63 expression in 16 BCCs, one keratoacanthoma and 13 SCCs. Methods: Immunohistochemistry according to the streptavidinbiotin-peroxidase technique, using the antibody 4A4 raised against all p63 isoforms, was performed. p63 expression was evaluated in epidermal cells and skin appendages. Semi-quantitative evaluation (–, π, ππ, πππ) of p63 expression in BCCs, keratoacanthoma and SCCs was carried out. Only nuclear expression was considered as specific. Results: p63 was expressed in the nuclei of epidermal basal and suprabasal cells...

p63 expression in normal skin and usual cutaneous carcinomas.

Reis-Filho, J; Torio, B; Albergaria, A; Schmitt, F
Fonte: Wiley Publicador: Wiley
Tipo: Artigo de Revista Científica
Publicado em //2002 ENG
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BACKGROUND: p63 is a p53 homologue that is mapped to chromosome 3q27. This gene encodes six different isoforms, which have either transactivating or dominant negative effects on p53-reporter genes. It has been described that in contrast to p53, p63 seems not to be associated with tumor predisposition, as neither p63 knockout mouse models nor germline p63 mutations are related to an increased risk of tumorigenesis. It has been demonstrated that p63 is a reliable keratinocyte stem cell marker and that it is involved in the maintenance of the stem cell population. Scant data on p63 expression in normal skin, basal cell carcinomas (BCCs), keratoacanthomas and squamous cell carcinomas (SCCs) have been reported. We herein evaluated p63 expression in 16 BCCs, one keratoacanthoma and 13 SCCs. METHODS: Immunohistochemistry according to the streptavidin-biotin-peroxidase technique, using the antibody 4A4 raised against all p63 isoforms, was performed. p63 expression was evaluated in epidermal cells and skin appendages. Semi-quantitative evaluation (-, +, ++, +++) of p63 expression in BCCs, keratoacanthoma and SCCs was carried out. Only nuclear expression was considered as specific. RESULTS: p63 was expressed in the nuclei of epidermal basal and suprabasal cells...

Does the correlation between EBNA-1 and p63 expression in breast carcinomas provide a clue to tumorigenesis in Epstein-Barr virus-related breast malignancies?

Ribeiro-Silva,A.; Ramalho,L.N.Z.; Garcia,S.B.; Zucoloto,S.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2004 EN
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Several investigators have identified Epstein-Barr virus (EBV) particles in breast carcinomas, a fact that supports a role for EBV in mammary tumorigenesis. The possible mechanism involved in this process is not clear. The present study was carried out in an attempt to determine whether there is a relationship between latent infection with EBV and p53 and p63 expression in breast carcinomas. Immunohistochemistry developed with 3.3-diaminobenzidine tetrahydrochloride was performed in 85 formalin-fixed paraffin-embedded breast carcinomas using anti-EBV EBNA-1, anti-p63, anti-p53, anti-estrogen receptor (ER) and anti-progesterone receptor (PR) antibodies. The cases were selected to represent each of the various histologic types: intraductal carcinoma (N = 12), grade I invasive ductal carcinoma (N = 15), grade II invasive ductal carcinoma (N = 15), grade III invasive ductal carcinoma (N = 15), tubular carcinoma (N = 8), lobular carcinoma (N = 10), and medullary carcinoma (N = 10). The ductal breast carcinomas were graded I, II and III based on the Scarff-Bloom and Richardson grading system modified by Elston and Ellis. One slide containing at least 1000 neoplastic cells was examined in each case. ER, PR, p63, p53 and EBNA-1 were positive in 60...

A família do p53: aspectos estruturais e funcionais do p73 e do p63

Ribeiro-Silva,Alfredo; Zucoloto,Sérgio
Fonte: Sociedade Brasileira de Patologia Clínica; Sociedade Brasileira de Patologia; Sociedade Brasileira de Citopatologia Publicador: Sociedade Brasileira de Patologia Clínica; Sociedade Brasileira de Patologia; Sociedade Brasileira de Citopatologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2003 PT
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O p53 é um gene regulador chave do ciclo celular que, quando sofre mutações, leva ao desenvolvimento de neoplasias, atuando, portanto, como um gene supressor tumoral em condições normais. Recentemente foram identificados genes homólogos ao p53 denominados p73 e p63, provavelmente oriundos de um gene ancestral comum. Apesar da grande homologia estrutural, os membros da família do p53 possuem diferenças funcionais entre si. O presente artigo tem por finalidade discorrer sobre os principais aspectos estruturais e funcionais do p73 e do p63, ressaltando seus papéis na tumorigênese humana. O p73 ativa vários genes responsivos ao p53 e, quando superexpresso, inibe a ação do p53. Raramente encontra-se mutado em neoplasias, e seu papel na tumorigênese humana ainda é motivo de controvérsias. O p63 não é um gene supressor tumoral clássico, sendo essencial para a manutenção de uma população de células precursoras (células-tronco) em vários tecidos epiteliais. O p63 marca as células basais de vários órgãos epiteliais, como a pele e a próstata, podendo ser considerado um marcador de indiferenciação celular. O p63 é um marcador recentemente descrito e ainda requer maior investigação para determinar seu papel no desenvolvimento de neoplasias em humanos.

Role of P63 (CKAP4) in binding of surfactant protein-A to type II pneumocytes

Bates, Sandra R.; Kazi, Altaf S.; Tao, Jian-Qin; Yu, Kevin J.; Gonder, Daniel S.; Feinstein, Sheldon I.; Fisher, Aron B.
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
EN
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We have recently described a putative receptor for lung surfactant protein-A (SP-A) on rat type II pneumocytes. The receptor, P63, is a 63-kDa type II transmembrane protein. Coincubation of type II cells with P63 antibody (Ab) reversed the inhibitory effect of SP-A on secretagogue-stimulated surfactant secretion from type II cells. To further characterize SP-A interactions with P63, we expressed recombinant P63 protein in Escherichia coli and generated antibodies to P63. Immunogold electron microscopy confirmed endoplasmic reticulum and plasma membrane localization of P63 in type II cells with prominent labeling of microvilli. Binding characteristics of iodinated SP-A to type II cells in the presence of P63 Ab were determined. Binding (4°C, 1 h) of 125I-SP-A to type II cells demonstrated both specific (calcium-dependent) and nonspecific (calcium-independent) components. Ab to P63 protein blocked the specific binding of 125I-SP-A to type II cells and did not change the nonspecific SP-A association. A549 cells, a pneumocyte model cell line, expressed substantial levels of P63 and demonstrated specific binding of 125I-SP-A that was inhibited by the P63 Ab. The secretagogue (cAMP)-stimulated increase in calcium-dependent binding of SP-A to type II cells was blocked by the presence of P63 Ab. Transfection of type II cells with small interfering RNA to P63 reduced P63 protein expression...

Differential effects of p63 mutants on transactivation of p53 and/or p63 responsive genes

Khokhar, Shama K; Kommagani, Ramakrishna; Kadakia, Madhavi P
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/2008 EN
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p63, known to play a role in development, has more recently also been implicated in cancer progression. Mutations in p63 have been shown to be responsible for several human developmental diseases. Differential splicing of the p63 gene gives rise to p63 isoforms, which can act either as tumor suppressors or as oncogene. In this report, we studied the effects of naturally occurring TAp63γ mutants on the regulation of p53/p63 and p63 specific target genes. We observed significant differences among p63 mutants to regulate the p53/p63 and p63 specific target genes. Additionally, we observed a differential effect of p63 mutants on wildtype-p63-mediated induction of p53/p63 and p63 specific target genes. We also demonstrated that these mutants differentially regulate the binding of wildtype p63 to the promoter of target genes. Furthermore, the effects of these mutants on cell death and survival were consistent with their ability to regulate the downstream targets when compared to wildtype TAp63γ. In summary, our data demonstrate that p63 mutants exhibit differential effects on p63 and p53/p63 specific target genes and on the induction of apoptosis, and provide further insight into the function of p63.

Special AT-rich Binding Protein-2 (SATB2) Differentially Affects Disease-causing p63 Mutant Proteins*

Chung, Jacky; Grant, R. Ian; Kaplan, David R.; Irwin, Meredith S.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
EN
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p63, a p53 family member, is critical for proper skin and limb development and directly regulates gene expression in the ectoderm. Mice lacking p63 exhibit skin and craniofacial defects including cleft palate. In humans p63 mutations are associated with several distinct developmental syndromes. p63 sterile-α-motif domain, AEC (ankyloblepharon-ectodermal dysplasia-clefting)-associated mutations are associated with a high prevalence of orofacial clefting disorders, which are less common in EEC (ectrodactyly-ectodermal dysplasia-clefting) patients with DNA binding domain p63 mutations. However, the mechanisms by which these mutations differentially influence p63 function remain unclear, and interactions with other proteins implicated in craniofacial development have not been identified. Here, we show that AEC p63 mutations affect the ability of the p63 protein to interact with special AT-rich binding protein-2 (SATB2), which has recently also been implicated in the development of cleft palate. p63 and SATB2 are co-expressed early in development in the ectoderm of the first and second branchial arches, two essential sites where signaling is required for craniofacial patterning. SATB2 attenuates p63-mediated gene expression of perp (p53 apoptosis effector related to PMP-22)...

p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

Yallowitz, A R; Alexandrova, E M; Talos, F; Xu, S; Marchenko, N D; Moll, U M
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN
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In embryogenesis, p63 is essential to develop mammary glands. In the adult mammary gland, p63 is highly expressed in the basal cell layer that comprises myoepithelial and interspersed stem/progenitor cells, and has limited expression in luminal epithelial cells. In adult skin, p63 has a crucial role in the maintenance of epithelial stem cells. However, it is unclear whether p63 also has an equivalent role as a stem/progenitor cell factor in adult mammary epithelium. We show that p63 is essential in vivo for the survival and maintenance of parity-identified mammary epithelial cells (PI-MECs), a pregnancy-induced heterogeneous population that survives post-lactational involution and contain multipotent progenitors that give rise to alveoli and ducts in subsequent pregnancies. p63+/− glands are normal in virgin, pregnant and lactating states. Importantly, however, during the apoptotic phase of post-lactational involution p63+/− glands show a threefold increase in epithelial cell death, concomitant with increased activation of the oncostatin M/Stat3 and p53 pro-apoptotic pathways, which are responsible for this phase. Thus, p63 is a physiologic antagonist of these pathways specifically in this regressive stage. After the restructuring phase when involution is complete...

The Prostate Basal Cell (BC) Heterogeneity and the p63-Positive BC Differentiation Spectrum in Mice

Lee, Dong-Kee; Liu, Yonghong; Liao, Lan; Wang, Fen; Xu, Jianming
Fonte: Ivyspring International Publisher Publicador: Ivyspring International Publisher
Tipo: Artigo de Revista Científica
Publicado em 06/09/2014 EN
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The prostate epithelium is composed of basal (BC), luminal (LEC), and neuroendocrine (NEC) cells. It is unclear how many subtypes of BCs in the prostate and which subtype of BCs contains the main stem cell niche in the adult prostate. Here we report seven BC subpopulations according to their p63, cytokeratin 14 (K14) and K5 expression patterns, including p63-positive/K14-negative/K5-negative (p63+/K14-/K5-), p63-/K14+/K5-, p63-/K14-/K5+, p63+/K14+/K5-, p63+/K14-/K5+, p63-/K14+/K5+, and p63+/K14+/K5+ BCs. We generated a p63-CreERT2 knock-in mouse line that expresses tamoxifen-inducible Cre activity in the p63-expressing cells, including the prostate BCs. We then crossbred this line with ROSA26R mice, and generated p63-CreERT2×ROSA26R bi-genic mice harboring the Cre-activated β-galactosidase reporter gene. We treated these bi-genic mice with tamoxifen to mark the p63+ BCs at different ages or under different hormonal conditions, and then traced the lineage differentiation of these genetically labeled BCs. We discovered that these p63+ BCs contain self-renewable stem cells in culture and efficiently differentiated into LECs, NECs and BCs in the postnatal, adult and re-generating mouse prostates. Therefore, BC population contains heterogeneous BCs that express different combinations of the p63...

Epithelial Cells Derived from Human Embryonic Stem Cells Display P16INK4A Senescence, Hypermotility, and Differentiation Properties Shared by Many P63+ Somatic Cell Types

Dabelsteen, Sally; Hercule, Paula; Barron, Patricia; Rice, Meghan; Dorsainville, Gregory; Rheinwald, James George
Fonte: Wiley-Blackwell Publicador: Wiley-Blackwell
Tipo: Artigo de Revista Científica
EN_US
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Human embryonic stem (hES) cells can generate cells expressing p63, K14, and involucrin, which have been proposed to be keratinocytes. Although these hES-derived, keratinocyte-like (hESderK) cells form epithelioid colonies when cultured in a fibroblast feeder system optimal for normal tissue-derived keratinocytes, they have a very short replicative lifespan unless engineered to express HPV16 E6E7. We report here that hESderK cells undergo senescence associated with p16INK4A expression, unrelated to telomere status. Transduction to express bmi1, a repressor of the p16INK4A/p14ARF locus, conferred upon hESderK cells and keratinocytes a substantially extended lifespan. When exposed to transforming growth factor beta or to an incompletely processed form of Laminin-332, three lifespan-extended or immortalized hESderK lines that we studied became directionally hypermotile, a wound healing and invasion response previously characterized in keratinocytes. In organotypic culture, hESderK cells stratified and expressed involucrin and K10, as do epidermal keratinocytes in vivo. However, their growth requirements were less stringent than keratinocytes. We then extended the comparison to endoderm-derived, p63+/K14+ urothelial and tracheobronchial epithelial cells. Primary and immortalized lines of these cell types had growth requirements and hypermotility responses similar to keratinocytes and bmi1 expression facilitated their immortalization by engineering to express the catalytic subunit of telomerase (TERT). In organotypic culture...

Mutant p53 uses p63 as a molecular chaperone to alter gene expression and induce a pro-invasive secretome

Neilsen, P.; Noll, J.; Suetani, R.; Schulz, R.; Al-ejeh, F.; Evdokiou, A.; Lane, D.; Callen, D.
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em //2011 EN
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Mutations in the TP53 gene commonly result in the expression of a full-length protein that drives cancer cell invasion and metastasis. Herein, we have deciphered the global landscape of transcriptional regulation by mutant p53 through the application of a panel of isogenic H1299 derivatives with inducible expression of several common cancer-associated p53 mutants. We found that the ability of mutant p53 to alter the transcriptional profile of cancer cells is remarkably conserved across different p53 mutants. The mutant p53 transcriptional landscape was nested within a small subset of wild-type p53 responsive genes, suggesting that the oncogenic properties of mutant p53 are conferred by retaining its ability to regulate a defined set of p53 target genes. These mutant p53 target genes were shown to converge upon a p63 signalling axis. Both mutant p53 and wild-type p63 were co-recruited to the promoters of these target genes, thus providing a molecular basis for their selective regulation by mutant p53. We demonstrate that mutant p53 manipulates the gene expression pattern of cancer cells to facilitate invasion through the release of a pro-invasive secretome into the tumor microenvironment. Collectively, this study provides mechanistic insight into the complex nature of transcriptional regulation by mutant p53 and implicates a role for tumor-derived p53 mutations in the manipulation of the cancer cell secretome.; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282078/; Paul M. Neilsen...

Molekulare Mechanismen in Zelldifferenzierung und Zellteilung; Molecular Mechanisms in Cell Differentiation and Cell Division

Kettenbach, Arminja Nadine
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
DE_DE
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p63 ist eines von drei Mitgliedern der p53 Familie von Transkriptionsfaktoren. Die Transkription des p63 Gens führt zu zwei verschiedenen Isoformen, der Isoform TA-p63 mit einer N-terminalen Transaktivierungsdomäne und der Isoform DeltaN-p63 ohne diese Domäne. Die hier beschriebene Untersuchung der Expression von p63 in Geweben und die Studie von p63-defizienten Mäusen zeigte, dass p63 in der Entwicklung von epithelialen Geweben, des Schädels und der Extremitäten eine wichtige Rolle spielt. Die Bedeutung von p63 in diesen Vorgängen wurde weiterhin verdeutlicht durch das Auftreten von p63 Mutationen in der menschlichen Keimbahn, die zu schweren Defekten in der Entwicklung von Extremitäten und zu epidermalen Fehlbildungen führen. Die genaue Funktion von p63 in der epidermalen Entwicklung ist noch immer stark umstritten. Während einerseits p63 als entscheidender Faktor in der Differenzierung des embryonalen Ektoderms zu epidermalen Geweben beschrieben wird, wird es andererseits als Stammzellfaktor für die Aufrechterhaltung des Teilungsvermögens und der Regeneration von epidermalen Stammzellen beschrieben. Darüber hinaus existieren unterschiedliche Meinungen zu der jeweiligen Bedeutung der TA- und der DeltaN-p63-Isoform in diesen Prozessen. Jüngste Studien haben gefunden...

Immunohistochemical expression of p63, epidermal growth factor receptor (EGFR) and notch-1 in radicular cysts, dentigerous cysts and keratocystic odontogenic tumors

Gonçalves,Cláudia Kallás; Fregnani,Eduardo Rodrigues; Leon,Jorge Esquiche; Silva-Sousa,Yara Teresinha Corrêa; Perez,Danyel Elias da Cruz
Fonte: Fundação Odontológica de Ribeirão Preto Publicador: Fundação Odontológica de Ribeirão Preto
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2012 EN
Relevância na Pesquisa
37.4389%
The aim of this study was to assess the immunohistochemical expression of p63 protein, epidermal growth factor receptor (EGFR) and Notch-1 in the epithelial lining of radicular cysts (RC), dentigerous cysts (DC) and keratocystic odontogenic tumors (KOT). For this study, 35 RC, 22 DC and 17 KOT were used. The clinical and epidemiological data were collected from the patient charts filed in the Oral Pathology Laboratory, University of Ribeirão Preto, Brazil. Immunohistochemical reactions against the p63, EGFR and Notch-1 were performed in 3-µm-thick histological sections. The slides were evaluated according to the following criteria: negative: <5% of positive cells, low expression: 5-50% of positive cells, and high expression: >50% of positive cells. Moreover, the intensity of EGFR and Notch-1 expressions was also evaluated. Fisher's exact test and Spearman's correlation coefficients were used for statistical analysis, considering a significance level of 5%. Almost all cases demonstrated p63, EGFR and Notch-1 expressions. The p63 expression was significantly higher in KOT (p<0.001). Positive correlation between these immunomarkers was observed. These findings suggest the participation of p63, EGFR and Notch-1 in the development...