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PubMed2005

The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage.

The transcriptional coactivator Yes-associated protein (YAP) has been shown to interact with and to enhance p73-dependent apoptosis in response to DNA damage. Here, we show that YAP requires the promyelocytic leukemia gene (PML) and nuclear body localization to coactivate p73. YAP imparts selectivity to p73 by promoting the activation of a subset of p53 and/or p73 target promoters. Endogenous p73, YAP, and p300 proteins are concomitantly recruited onto the regulatory regions of the apoptotic target gene p53AIP1 only when cells are exposed to apoptotic conditions. Silencing of YAP by specific siRNA impairs p300 recruitment and reduces histone acetylation on the p53AIP1 target gene, resulting in delayed or reduced apoptosis mediated by p73. We also found that YAP contributes to the DNA damage-induced accumulation of p73 and potentiates the p300-mediated acetylation of p73. Altogether, our findings identify YAP as a key determinant of p73 gene targeting in response to DNA damage.

Acetylation↗
PubMed1997

Saccharomyces cerevisiae basic region-leucine zipper protein regulatory networks converge at the ATR1 structural gene.

Saccharomyces cerevisiae cells express a family of transcription factors belonging to the basic region-leucine zipper family. Two of these proteins, yAP-1 and Gcn4p, are known to be involved in oxidative stress tolerance and general control of amino acid biosynthesis, respectively. Strains lacking the YAP1 or GCN4 structural gene have very different phenotypes, which have been taken as evidence that these transcriptional regulatory proteins control separate batteries of target genes. In this study, we provide evidence that both yAP-1 and Gcn4p control the expression of a putative integral membrane protein, Atr1p. Both yAP-1 and Gcn4p can elevate resistance to 3-amino-1,2,4-triazole and 4-nitroquinoline-N-oxide but only if the ATR1 gene is intact. Expression of ATR1 is enhanced in the presence of constitutively active alleles of YAP1 and GCN4. Regulation of ATR1 transcription by yAP-1 and Gcn4p occurs through a common DNA element related to the yAP-1 recognition element found upstream of other yAP-1-regulated genes. These data provide the first indication of overlap between the regulatory networks defined by yAP-1 and Gcn4p.

4-Nitroquinoline-1-oxide↗
PubMed1997

The geographic distribution of human Y chromosome variation.

We examined variation on the nonrecombining portion of the human Y chromosome to investigate human evolution during the last 200,000 years. The Y-specific polymorphic sites included the Y Alu insertional polymorphism or "YAP" element (DYS287), the poly(A) tail associated with the YAP element, three point mutations in close association with the YAP insertion site, an A-G polymorphic transition (DYS271), and a tetranucleotide microsatellite (DYS19). Global variation at the five bi-allelic sites (DYS271, DYS287, and the three point mutations) gave rise to five "YAP haplotypes" in 60 populations from Africa, Europe, Asia, Australasia, and the New World (n = 1500). Combining the multi-allelic variation at the microsatellite loci (poly(A) tail and DYS19) with the YAP haplotypes resulted in a total of 27 "combination haplotypes". All five of the YAP haplotypes and 21 of the 27 combination haplotypes were found in African populations, which had greater haplotype diversity than did populations from other geographical locations. Only subsets of the five YAP haplotypes were found outside of Africa. Patterns of observed variation were compatible with a variety of hypotheses, including multiple human migrations and range expansions.

Gene Frequency↗
PubMed2000

[Haplotypes of two diallelic Y chromosome loci in the indigenous and migrant populations of Siberia].

Two diallelic Y-chromosome markers, the Y Alu polymorphism (YAP) and the T-C transition (Tat), were analyzed in the indigenous (Tuvinian, Buryat, Northern Altaic, and Tatar) and migrant (Slavic) populations of Siberia. A high frequency of the allele C was revealed in several indigenous populations (25-55%) and in Russians (20.8%). The YAP+ allele occurred at a surprisingly high frequency (31.4%) and was completely linked with the C allele in Buryats. The YAP+ chromosome was also found in the Tuvinian population (1.5%). The two diallelic loci showed a marked linkage disequilibrium (D = 92.4%) in the total sample. The YAP-/T and YAP-/C haplotypes prevailed in both indigenous and migrant populations: their respective frequencies were 80.4 and 19.6% in the Slavic population and 71.8 and 19.9%, respectively, in the indigenous one. The YAP+/C (7.8%) and YAP+/T (0.5%) haplotypes were found only in the indigenous population. An appreciable heterogeneity in haplotype frequency distribution between regional subpopulations was revealed in Russians, Tuvinians, and Buryats. The origin and evolution of Y-chromosome lines in Northern Asia are considered.

Alleles↗
PubMed1996

Establishment and characterization of a novel human promonocytic cell line from peripheral blood of a patient with psoriasis.

Human monocyte/macrophage lineages have unique phagocytic and immune-regulatory functions. We established a promonocytic cell line from the peripheral blood of a patient with psoriasis vulgaris. The newly established cells, termed YAP cells, grew in a suspension culture. In Wright-Giemsa-stained preparations, YAP cells were round or polygonal in shape. Transmission electron microscopy showed that the cells had clear nuclei with well-defined nucleoli. There were frequent mitochondria, a relatively abundant endoplasmic reticulum profile, free ribosomes and an occasional Golgi apparatus. Cytochemical studies showed a positive reaction for alpha-naphthyl butyrate esterase, which was completely inhibited by sodium fluoride, a diffuse positive reaction for periodic acid-Schiff, and a negative result for alkaline phosphatase and peroxidase. A large population of YAP cells reacted with the CD4, CD11b, CD25 and CD33 surface markers, but not with CD2, CD3, CD8 or CD19. We also found that YAP cells produced considerable amounts of TNF alpha, which was detected in the culture supernatant when the cells were treated with 1 ng/ml 12-O-tetradecanoylphorbol-13-acetate (TPA). Chromosome analyses showed that YAP cells contained a variety of marker chromosomes. It should be stressed that YAP cells were derived from a patient with a non-neoplastic disorder, whereas most monocytic cell lines previously reported are of malignant origin. This newly established cell line might be valuable for studying the pathogenesis of psoriasis, especially the role of monocytes/macrophages in the aetiology of the disease.

Adult↗
PubMed2006

[Polymorphism of DYS287 on Y chromosome in 28 ethnic populations of China].

OBJECTIVE: To investigate the polymorphism of DYS287 among 28 ethnic populations in 9 provinces of China. METHOD: YAP element was detected by Touchdown PCR amplification and 2% agarose gel electrophoresis. RESULTS: YAP+ frequencies in these ethnic populations were as follows: Zang 36.7%, Tu 23.8%, Yi 18.4%, Pumi 11.3%, Tajik 7.4%, Bai 6.7%, Jino 5.1%, Shandong Han 4%, Mulao 2.7%, and Maonan 1.3%. The rest ethnic populations in our study, including Gansu Han, Yunnan Han, Zhuangzu, Daizu, Lizu, Nuzu, Lisu, Naxi, Lahu, Dulong, Hani, Shezu, Weiwuer, Sala, Kerkizi, Dongxiang, Vazu, and Korea didn't carry YAP + element. CONCLUSIONS: Zangzu, Tuzu, Yizu, Pumi, Jino, and Baizu, which belong to Sino-Tibetan language family, carry a high YAP + frequency. Sala, Tuzu, and Tajik, regarded as Central Asia by origin in history and linguistics, also have a high YAP + frequency. Mulao and Maonan, which origin from "Baiyue" ancient ethnic groups, also have a considerable YAP + frequency.

Alu Elements↗
PubMed2004

Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level.

It has been proposed that ligand-dependent Regulated Intramembrane Proteolysis (RIP) of ErbB-4 receptors generates 80 kDa Intra-Cellular Domains (E4.ICDs) that relocate to the nuclear compartments where they implement the signaling abilities of the ErbB-4 receptors. The E4.ICD may directly regulate gene transcription or, in an alternative scenario, the tyrosine kinase activity of E4.ICDs may target proteins involved in transcriptional regulation upon its relocation into the nucleus. We have identified the transcriptional coactivator YAP65, here referred as YAP (Yes Associated Protein), as binding partner of ErbB-4 in a two hybrid screening in yeast. Interaction between YAP and ErbB-4 occurs via the WW domain of YAP and the PPPPY at positions 1297-1301 and the PPPAY at positions 1052-1056 of the amino acid sequence of the Cyt-1 isoform of ErbB-4. Stechiometry of binding is regulated by the ligand-dependent phosphorylation of Tyr 1056 in the PPPAYTPM module that function as "biochemical switch" to decrease the association of YAP to ErbB-4. In principle, this novel interaction highlights new mechanisms of signaling propagation from the ErbB-4 receptors, offering supporting evidences that the E4.ICDs forms released following ligand-receptor engagement may recruit YAP and relocate to the nucleus to implement or regulate transcription.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains.

To understand the role of the Yes-associated protein (YAP), binding partners of its WW1 domain were isolated by a yeast two-hybrid screen. One of the interacting proteins was identified as p53-binding protein-2 (p53BP-2). YAP and p53BP-2 interacted in vitro and in vivo using their WW1 and SH3 domains, respectively. The YAP WW1 domain bound to the YPPPPY motif of p53BP-2, whereas the p53BP-2 SH3 domain interacted with the VPMRLR sequence of YAP, which is different from other known SH3 domain-binding motifs. By mutagenesis, we showed that this unusual SH3 domain interaction was due to the presence of three consecutive tryptophans located within the betaC strand of the SH3 domain. A point mutation within this triplet, W976R, restored the binding selectivity to the general consensus sequence for SH3 domains, the PXXP motif. A constitutively active form of c-Yes was observed to decrease the binding affinity between YAP and p53BP-2 using chloramphenicol acetyltransferase/enzyme-linked immunosorbent assay, whereas the overexpression of c-Yes did not modify this interaction. Since overexpression of an activated form of c-Yes resulted in tyrosine phosphorylation of p53BP-2, we propose that the p53BP-2 phosphorylation, possibly in the WW1 domain-binding motif, might negatively regulate the YAP.p53BP-2 complex.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Fast 3D-EM reconstruction using Planograms for stationary planar positron emission mammography camera.

At the University of Pisa we are building a PEM prototype, the YAP-PEM camera, consisting of two opposite 6 x 6 x 3 cm3 detector heads of 30 x 30 YAP:Ce finger crystals, 2 x 2 x 30 mm3 each. The camera will be equipped with breast compressors. The acquisition will be stationary. Compared with a whole body PET scanner, a planar Positron Emission Mammography (PEM) camera allows a better, easier and more flexible positioning around the breast in the vicinity of the tumor: this increases the sensitivity and solid angle coverage, and reduces cost. To avoid software rejection of data during the reconstruction, resulting in a reduced sensitivity, we adopted a 3D-EM reconstruction which uses all of the collected Lines Of Response (LORs). This skips the PSF distortion given by data rebinning procedures and/or Fourier methods. The traditional 3D-EM reconstruction requires several times the computation of the LOR-voxel correlation matrix, or probability matrix {p(ij)}; therefore is highly time-consuming. We use the sparse and symmetry properties of the matrix {p(ij)} to perform fast 3D-EM reconstruction. Geometrically, a 3D grid of cubic voxels (FOV) is crossed by several divergent 3D line sets (LORs). The symmetries occur when tracing different LORs produces the same p(ij) value. Parallel LORs of different sets cross the FOV in the same way, and the repetition of p(ij) values depends on the ratio between the tube and voxel sizes. By optimizing this ratio, the occurrence of symmetries is increased. We identify a nucleus of symmetry of LORs: for each set of symmetrical LORs we choose just one LOR to be put in the nucleus, while the others lie outside. All of the possible p(ij) values are obtainable by tracking only the LORs of this nucleus. The coordinates of the voxels of all of the other LORs are given by means of simple translation rules. Before making the reconstruction, we trace the LORs of the nucleus to find the intersecting voxels, whose p(ij) values are computed and stored with their voxel coordinates on a hard disk. Only the non-zero p(ij) are considered and their computation is performed just once. During the reconstruction, the stored values are loaded and are available in the random access memory for all of the operations of normalization, backprojection and projection: these are now performed rapidly, because the application of the translation rules is much faster than the probability computations. We tested the algorithm on Monte Carlo data fully simulating the typical YAP-PEM clinical condition. The adopted algorithm gives an excellent positioning capability for hot spots in the camera FOV. To use all of the possible skew LORs in the FOV avoids the software rejection of collected data. Reconstructed images indicate that a 5mm diameter tumor of 37 kBq/cm3, in an active breast with a 10:1 Tissue to Background ratio (T/B), with a 10 min acquisition, for a head distance of 5 cm, can be detected by the YAP-PEM with a SNR of 8.7+/-1.0. The obtained SNR values depend linearly on the tumor volume. The algorithm allows one to discriminate between two hot sources of 5.0 mm diameter if they do not lie on the same axis. The YAP-PEM is now in the assembly stage.

Algorithms↗
PubMed2005

A novel anticoagulant purified from fish protein hydrolysate inhibits factor XIIa and platelet aggregation.

A novel fish protein having anticoagulant and antiplatelet properties was enzymatically extracted from the marine fish, yellowfin sole (Limanda aspera) and purified to homogeneity producing an overall purification fold of 206.6. MALDI-TOF mass spectroscopic and SDS-PAGE analysis identified the purified protein as 12.01 kDa single-chain monomeric protein. It inhibited the activated coagulation factor XII (FXIIa) by forming an inactive complex regardless of Zn2+ mediation, and was named, yellowfin sole anticoagulant protein (YAP). In addition, YAP act to antagonize platelet membrane glycoprotein integrin, to arrest platelet aggregation. However, YAP was not able to block the adhesion of platelets to collagen, which mediate via major collagen receptors, GPIa/IIa on platelet membrane. Furthermore, YAP did not possess plasminogen activator-like activity to activate fibrinolysis. In fact, our findings indicate that YAP binds with FXIIa and platelet membrane integrins to inhibit thrombosis in vitro.

Animals↗
PubMed2006

Effects of Yb concentration on the fluorescence spectra of Yb-doped YAlO3 single crystals.

0.5 at.% Yb:YAlO(3)(YAP), 5 at.% Yb:YAP and 15 at.% Yb:YAP were grown using the Czochralski method. Their absorption and fluorescence spectra were measured at room temperature and their emission line shape was calculated using the method of reciprocity. It was observed that the fluorescence spectra changed appreciably with the increasing of Yb concentration. For 0.5 at.% Yb:YAP, the line shape of fluorescence is very similar with the calculated emission line shape; with the increasing of Yb doping concentration, the line shape of fluorescence is very different from the calculated emission line shape. These phenomena are caused by the strong self-absorption at 979 and 999 nm for Yb:YAP.

Aluminum↗
PubMed2003

Rare deep-rooting Y chromosome lineages in humans: lessons for phylogeography.

There has been considerable debate on the geographic origin of the human Y chromosome Alu polymorphism (YAP). Here we report a new, very rare deep-rooting haplogroup within the YAP clade, together with data on other deep-rooting YAP clades. The new haplogroup, found so far in only five Nigerians, is the least-derived YAP haplogroup according to currently known binary markers. However, because the interior branching order of the Y chromosome genealogical tree remains unknown, it is impossible to impute the origin of the YAP clade with certainty. We discuss the problems presented by rare deep-rooting lineages for Y chromosome phylogeography.

Biological Evolution↗
PubMed1994

A recent insertion of an alu element on the Y chromosome is a useful marker for human population studies.

A member of the Alu family of repeated DNA elements has been identified on the long arm of the human Y chromosome, Yq11. This element, referred to as the Y Alu polymorphic (YAP) element, is present at a specific site on the Y chromosome in some humans and is absent in others. Phylogenetic comparisons with other Alu sequences reveal that the YAP element is a member of the polymorphic subfamily-3 (PSF-3), a previously undefined subfamily of Alu elements. The evolutionary relationships of PSF-3 to other Alu subfamilies support the hypothesis that recently inserted elements result from multiple source genes. The frequency of the YAP element is described in 340 individuals from 14 populations, and the data are combined with those from other populations. There is both significant heterogeneity among populations and a clear pattern in the frequencies of the insertion: sub-Saharan Africans have the highest frequencies, followed by northern Africans, Europeans, Oceanians, and Asians. An interesting exception is the relatively high frequency of the YAP element in Japanese. The greatest genetic distance is observed between the African and non-African populations. The YAP is especially useful for studying human population history from the perspective of male lineages.

Animals↗
PubMed1989

Yeast YAP1 encodes a novel form of the jun family of transcriptional activator proteins.

The jun family of transcriptional activators includes mammalian AP-1 as well as the yeast regulatory protein GCN4. Recently, an additional transcriptional activator has been found in yeast that recognizes the TGACTCA sequence element common in GCN4/AP-1 sites. This factor was designated yAP-1. The structural gene for yAP-1 has now been isolated and characterized. The deduced amino acid sequence predicts a protein of 650 residues, considerably larger than GCN4 or c-Jun. The amino terminus of yAP-1 is homologous to the carboxy-terminal DNA-binding domains of GCN4 and c-Jun. Disruption of the YAP1 gene demonstrates this gene is not essential but is required for AP-1 recognition element-dependent transcriptional activation. DNA-affinity blots of proteins from YAP1 cells suggest the presence of additional TGACTCA-binding proteins other than GCN4 and yAP-1. Furthermore, expression of at least one of these related DNA-binding proteins appears to be under control of yAP-1.

Amino Acid Sequence↗
PubMed2002

Lack of association between Y chromosome Alu insertion polymorphism and hypertension.

There is an inherited paternal predisposition to hypertension. Y chromosome alphoid satellite variation was recently reported to be linked to diastolic blood pressure. To determine whether there is also a Y chromosome marker linked to hypertension, we investigated the prevalence of the Y chromosome Alu insertion polymorphism (YAP) at DYS287 and its association with hypertension in the Aomori population in the northern area of Honshu Island, Japan. YAP was present in 98 of 285 male residents and absent in the rest. The YAP prevalence in the present study would appear to suggest that the present study population represents the general male population in central Japan. Within the study population, there were 110 hypertensive subjects and 104 normotensive subjects. YAP frequency in the hypertensive subjects was not different from that in the normotensive subjects. These results suggest that the YAP is not likely to be a genetic-susceptibility factor for hypertension in the Aomori population.

Adult↗
PubMed2001

[Haplotype of Y-chromosomes in the Central Asia population].

The distribution of alleles and haplotypes of three diallellic Y-specific loci (YAP, DYF155S2, and Tat) in the populations of Kyrgyz, Uzbeks and Tajiks was analyzed. In Kyrgyzes and Uzbeks, a relatively high frequency of the DYF155S2 deletion (20 and 12.5%, respectively) and the C allele at the Tat locus (11.2 and 8.3%, respectively) were revealed. In the populations of southern Kyrgyzes and Uzbeks, two chromosomes carrying the YAP+ allele were detected. In both cases the YAP+ allele was found within the YAP+/DYF155S2+/TatT haplotype. The Tajik population was monomorphic in respect to the polymorphisms studied. The Tajiks demonstrated the presence of only the YAP-/DYF155S2+/TatT haplotype. This haplotype appeared to be most frequent in Kyrgyz (78.8%) and Uzbeks (83.3%). The question on the origin and the distribution of Y-chromosome variants in Eurasia are discussed.

Asia, Central↗
PubMed1994

Transcriptional activation mediated by the yeast AP-1 protein is required for normal cadmium tolerance.

The yeast YAP1 gene encodes a transcriptional regulatory protein that utilizes a basic region-leucine zipper (bZip) DNA-binding domain to recognize its cognate DNA element. A synthetic reporter gene containing a SV40 AP-1 response element (ARE) cloned upstream of a TRP5 promoter-lacZ gene fusion shows yAP-1-dependent transactivation in vivo. Recent work has shown that changes in the gene dosage of this factor can dramatically alter the ability of a cell to tolerate a host of toxic agents including cadmium, cycloheximide, and sulfometuron methyl. We have focused on the YAP1-dependent cadmium resistance as cells that lack a functional YAP1 gene are hypersensitive to this metal. Deletion mapping experiments define two domains in the carboxyl-terminal region of the yAP-1 protein that are required for normal cadmium tolerance and ARE-TRP5-lacZ expression. Single amino acid substitutions in the bZip domain of yAP-1 indicate that this region is required for normal DNA binding and in vivo function of the protein. Replacement of a non-canonical asparagine with leucine in the yAP-1 leucine zipper leads to production of a defective protein. A substitution mutation in the basic domain converts this mutant protein into a dominant negative factor. The ability of yAP-1 to act as a positive regulator of transcription is required for its biological action.

Base Sequence↗
PubMed1995

Characterization of a novel protein-binding module--the WW domain.

We have identified, characterized and cloned human, mouse and chicken cDNA of a novel protein that binds to the Src homology domain 3 (SH3) of the Yes proto-oncogene product. We subsequently named it YAP for Yes-associated protein. Analysis of the YAP sequence revealed a protein module that was found in various structural, regulatory and signaling molecules. Because one of the prominent features of this sequence motif is the presence of two conserved tryptophans (W), we named it the WW domain. Using a functional screen of a cDNA expression library, we have identified two putative ligands of the WW domain of YAP which we named WBP-1 and WBP-2. Peptide sequence comparison between the two partial clones revealed a homologous proline-rich region. Binding assays and site-specific mutagenesis have shown that the proline-rich motif binds with relatively high affinity and specificity to the WW domain of YAP, with a preliminary consensus that is different from the SH3-binding PXXP motif. This suggests that the WW domain has a role in mediating protein-protein interactions via proline-rich regions, similar but distinct from Src homology 3 (SH3) domains. Based on this finding, we hypothesize that additional protein modules exist and that they could be isolated using proline-rich peptides as functional probes.

Adaptor Proteins, Signal Transducing↗