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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate stem cell antigen (PSCA, named for its strong sequence homology to the thymocyte marker stem cell antigen 2) is a cell surface antigen expressed in normal prostate and associated with human and murine prostate cancer. To begin to investigate a possible link between PSCA expression in normal prostate and prostate carcinogenesis, we characterized the phenotype and proliferative behavior of normal PSCA-expressing prostate epithelial cells (PrEC) in tissue culture. PSCA was expressed in a subset of prostate epithelial cells that coexpress basal and secretory cytokeratins. PSCA-positive cells were the direct progeny of PSCA-negative cells and were characterized by a more differentiated morphology and a slower proliferative rate than PSCA-negative cells. Although PSCA-positive cells continued to express basal cell markers such as CD44, they lost expression of the basal cell marker p63. In contrast, expression of prostate specific antigen and androgen receptor transcripts was detectable in PSCA-positive PrEC. These findings suggest that PSCA is a unique marker of an intermediate subpopulation of PrEC in transition from a basal to a terminally differentiated secretory phenotype and may be a useful marker for the study of normal and malignant prostate development.
Mol Cancer Res 2002 Dec
PMID:Prostate stem cell antigen is a marker of late intermediate prostate epithelial cells. 1249 58

Metaplastic carcinomas of the breast (MCBs) are unusual neoplasms characterized by an admixture of glandular epithelial components, which frequently exhibit features of squamous differentiation, and mesenchymal malignant components. Regardless of the presence of myoepithelial features in MCB, no consensus concerning their putative histogenesis has yet been achieved. Recently, novel putative myoepithelial markers have been developed, including p63, maspin, and P-cadherin. We assessed the expression of these myoepithelial markers in MCBs and compared their expression with classic myoepithelial markers. Immunohistochemistry using the streptavidin-biotin-peroxidase complex technique with antibodies raised against p63, maspin, P-cadherin, actin (clones CGA7, 1A4 and HHF35), cytokeratin 14 (Ck14), and vimentin was performed on 16 MCBs (7 matrix-producing MCBs, 6 adenosquamous MCBs, and 3 MCBs with heterologous elements). In healthy breast lobules and ducts adjacent to the tumors, myoepithelial cells showed distinctive and consistent immunoreactivity for p63, maspin, P-cadherin, actin, S-100 protein, and Ck14. Matrix-producing MCBs were positive for maspin in all cases, for p63 in 4 of 7 cases, and for P-cadherin in 4 of 7 cases. Adenosquamous MCB showed immunoreactivity for p63, maspin, and P-cadherin in 5 of 6 cases. All novel myoepithelial markers and Ck14 decorated squamous cell islands. MCBs with heterologous elements were positive for p63 in 1 case, for maspin in all 3 cases, and for P-cadherin in 2 cases. All cases showed at least one of the novel myoepithelial markers. Eleven of 16 cases were positive for actin. Eleven of 14 cases reacted with Ck14, and all cases that stained for S-100 protein (9 of 9) and vimentin (13 of 13) were also positive. Based on our findings, the balance of probabilities favors that MCBs may have a basal or myoepithelial cell histogenesis and differentiation.
Appl Immunohistochem Mol Morphol 2003 Mar
PMID:Novel and classic myoepithelial/stem cell markers in metaplastic carcinomas of the breast. 1261 Mar 49

Epidermal stem cells (ESC) are responsible for maintaining skin cellular homeostasis, as they give rise to fast-dividing transit amplifying cells committed to terminal differentiation, while retaining their self-renewal capacity. However, no pure ESC cultures are available and no highly specific cytochemical marker was identified. We report here the experimental conditions allowing the selective enrichment in ESC, using cultured adult human keratinocytes. The main step was the selection of cells able to rapidly adhere to human collagen type IV in vitro. Thus, an increased proportion of putative ESC of about 65% was obtained, as demonstrated by p63 expression.
J Cell Mol Med
PMID:Stem cells (p63(+)) in keratinocyte cultures from human adult skin. 1261 43

p63 is a recently identified homolog of p53 that is found in the basal layer of several stratified epithelial tissues such as the epidermis, oral mucosa, prostate, and urogenital tract. Studies with p63(-/-) mice and analysis of several human autosomal-dominant disorders with germ line p63 mutations suggest p63 involvement in maintaining epidermal stem cell populations. The p63 gene encodes six splice variants with reported transactivating or dominant-negative activities. The goals of the current study were to determine the splice variants that are expressed in primary human epidermal keratinocytes (HEKs) and the biochemical activity p63 has in these epithelial cell populations. We found that the predominant splice variant expressed in HEKs was Delta Np63 alpha, and it was present as a phosphorylated protein. During HEK differentiation, Delta Np63 alpha and p53 levels decreased, while expression of p53 target genes p21 and 14-3-3 sigma increased. Delta Np63 alpha had transcriptional repressor activity in vitro, and this activity was reduced in Delta Np63 alpha proteins containing point mutations, corresponding to those found in patients with Hay-Wells syndrome. Further, we show that Delta Np63 alpha and p53 can bind the p21 and 14-3-3 sigma promoters in vitro and in vivo, with decreased binding of p63 to these promoters during HEK differentiation. These data suggest that Delta Np63 alpha acts as a transcriptional repressor at select growth regulatory gene promoters in HEKs, and this repression likely plays an important role in the proliferative capacity of basal keratinocytes.
Mol Cell Biol 2003 Apr
PMID:The Delta Np63 alpha phosphoprotein binds the p21 and 14-3-3 sigma promoters in vivo and has transcriptional repressor activity that is reduced by Hay-Wells syndrome-derived mutations. 1264 Jan 12

The methods outlined in this chapter are designed to facilitate the study of the transactivation and transrepression properties of p53 (as well as p63 and p73). Once a gene of interest is identified, its presumptive promoter region can be cloned upstream of a luciferase gene in a plasmid. The most common reason for transfection experiments is to study gene expression patterns in the presence or absence of a particular gene product (e.g., p53). Three methods of transfection are outlined in this chapter: (i) cationic lipofection; (ii) calcium phosphate precipitation; and (iii) BES precipitation. The first method is ideal for the study of transactivation and transrepression properties of p53 (or other transcription factors). The last two are more suited for experiments where larger numbers of transfected cells are needed. Several examples of transfections and their respective results are provided.
Methods Mol Biol 2003
PMID:Transactivation and transrepression studies with p53. 1282 27

We recently showed that ASPP1 and ASPP2 stimulate the apoptotic function of p53. We show here that ASPP1 and ASPP2 also induce apoptosis independently of p53. By binding to p63 and p73 in vitro and in vivo, ASPP1 and ASPP2 stimulate the transactivation function of p63 and p73 on the promoters of Bax, PIG3, and PUMA but not mdm2 or p21(WAF-1/CIP1). The expression of ASPP1 and ASPP2 also enhances the apoptotic function of p63 and p73 by selectively inducing the expression of endogenous p53 target genes, such as PIG3 and PUMA, but not mdm2 or p21(WAF-1/CIP1). Removal of endogenous p63 or p73 with RNA interference demonstrated that (16) the p53-independent apoptotic function of ASPP1 and ASPP2 is mediated mainly by p63 and p73. Hence, ASPP1 and ASPP2 are the first two identified common activators of all p53 family members. All these results suggest that ASPP1 and ASPP2 could suppress tumor growth even in tumors expressing mutant p53.
Mol Cell Biol 2004 Feb
PMID:ASPP1 and ASPP2: common activators of p53 family members. 1472 77

Molecular phylogenies based on the molecular clock require the comparison of orthologous genes. Orthologous and paralogous genes usually have very different evolutionary fates. In general, orthologs keep the same functions in species, whereas, particularly over a long time span, paralogs diverge functionally and may become pseudogenes or get lost. In eukaryotic genomes, because of the degree of redundancy of genetic information, homologous genes are grouped in gene families, the evolution of which may differ greatly between the various organisms. This implies that each gene in a species does not always have an ortholog in another species and thus, due to multiple duplication events following a speciation, many orthologous clades of paralogs are generated. We are often dealing with a one-to-many or many-to-many relationship between genes. In this paper, we analyze the evolution of two gene families, the p53 gene family and the porin gene family. The evolution of the p53 family shows a one-to-many gene relationship going from invertebrates to vertebrates. In invertebrates only a single gene has been found, while in vertebrates three members of the family, namely p53, p63, and p73, are present. The evolution of porin (VDAC) genes (VDAC1, VDAC2, and VDAC3) is an example of a many-to-many gene relationship going from yeast to mammals. However, the porin gene redundancy found in invertebrates and possibly in some fishes may indicate a tendency to duplicate the genetic material, rather than a real need for function innovation.
J Mol Evol 2003
PMID:Molecular clock and gene function. 1500 25

The tumor suppressor p53 is transcription factor composed of four identical subunits. The majority of the mutations in p53 are missense mutations that impair DNA binding. On the other hand, the p53-related p63 and p73 genes are rarely mutated, but many cell types express natural variants lacking the N-terminal transactivation domain (NDelta). Compelling evidence indicates that both the DNA binding-defective and NDelta mutants can impair the function of wild-type p53 in a dominant-negative manner. Interestingly, it is uncertain how many mutant subunit(s) a p53 tetramer can tolerate. In this study, we first made theoretical predictions based on the number of mutant p53 monomers needed to inactivate a tetramer and then tested how well the experimental data fit the predicted values. Surprisingly, these experiments reveal that DNA binding-defective p53 mutants (R249S and R273H) are very ineffective in impairing the transcriptional activity of p53: at least three mutants are required to inactivate a tetramer. In marked contrast, p53NDelta is a very potent inhibitor of p53: one NDelta subunit per tetramer is sufficient to abolish the transcriptional activity. DNA binding is not necessary for the NDelta proteins to inactivate p53. Similarly, NDelta variants of p63 and p73 are also powerful inhibitors of members of the p53 family. These results have important implications for our thinking about the mechanism of tumorigenesis involving missense p53 mutants or the N-terminally truncated isoforms.
Mol Cell Biol 2004 Apr
PMID:How many mutant p53 molecules are needed to inactivate a tetramer? 1506 Jan 72

p53 is the most commonly mutated gene in human cancer. After activation by cellular stresses such as DNA damage or oncogene activation, p53, a sequence-specific DNA-binding protein, induces the expression of target genes which mediate tumor suppression. Two recently identified p53 homologues, p63 and p73, appear to function similarly to p53, that is, they both activate target gene expression and suppress cell growth when overexpressed; however, the p63 and p73 genes are rarely mutated in human cancer and do not adhere to Knudson's classical model of a tumor suppressor gene. Recently, exciting observations suggest nonoverlapping functions for the family members. Herein, we outline the recent literatures identifying and characterizing both the common and distinct target genes of the p53 family transcription factors in relation to their signaling pathways.
Cell Mol Life Sci 2004 Apr
PMID:The common and distinct target genes of the p53 family transcription factors. 1509 6

Diagnosis of prostate needle biopsies can be challenging, particularly when the atypical areas of interest are very small. The utility of immunostains for high-molecular-weight cytokeratin (34betaE12) to highlight prostatic basal cells in these cases is well established, and recent reports also document the utility of immunostains for p63 (a marker that stains the nuclei of prostate basal cells) for this purpose. Several investigators have demonstrated that immunostaining for P504S, a cytoplasmic protein that is overexpressed in a high percentage of prostate cancers and in many cases of high-grade prostatic intraepithelial neoplasia (PIN), can also be of use in the diagnosis of prostate biopsies. Because of the cytoplasmic localization of P504S and nuclear localization of p63, the authors hypothesized that a cocktail of these two antibodies might allow simultaneous demonstration of P504S and p63 using a single immunostain. In this report the authors describe the successful use of a cocktail of p63/P504S for immunohistochemical staining of prostate tissue. Two different staining approaches were investigated, with essentially identical results. This cocktail localizes P504S in the cytoplasm of prostate carcinoma cells and high-grade PIN and demonstrates the nuclei of prostatic basal cells, providing information on both the status of P504S and the presence or absence of basal cells with a single immunostain. This cocktail can be of great utility in the examination of diagnostically challenging prostate specimens.
Appl Immunohistochem Mol Morphol 2004 Mar
PMID:Use of p63/P504S monoclonal antibody cocktail in immunohistochemical staining of prostate tissue. 1516 24


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