14,549 research outputs found
Transcription Factor AP-2 Regulatory Signatures in Breast Cancer
No full textPhDAP-2 transcription factors are highly conserved basic helix-span-helix proteins whose
members ((x, ß, y, S and c) are crucial regulators of bryonic development. They also
play an important role in human neoplasia. uohis ochemical studies have detected
high levels of AP-2y expression in primary tumo of breast cancer patients. This high
expression has been correlated with reduced survival in all patients and reduced survival
in an ERa positive subset treated with hormone therapy. In breast cancer cell lines, AP-
2 factors have been implicated in the regulation of the ERBB2 proto-oncogene and ERa.
In an effort to further understand the role of AP-2y in breast carcinoma, this study has
sought to identify additional AP-2 activated cellular pathways and ultimately novel
transcriptional targets for AP-2 through the use of gene expression profiling.
RNAi using three independent AP-2y targeting sequences, has been used to deplete AP-
2y levels in the ERa positive MCF-7 breast carcinoma cell line, chosen as it exclusively
expresses the AP-2y family member. Microarrays were then utilised to create an AP-2y
dependent transcription profile. Statistical comparisons between non-silencing control
siRNA and AP-2y targeting siRNA groups identified a total of 162 gene expression
changes (p<0.01). These changes implicate AP-2y in the control of cell cycle
progression and developmental signalling. Indeed a role for AP-2y in the control of cell
cycle, in particular at the GUS transition, has been verified using flow cytometry.
Several of these gene expression changes, including IGFBP3, Transgelin and
KIAA1324, have been confirmed using qPCR and immunoblotting.
Finally, elevated levels of p21 mRNA and protein have been observed following AP-2y
silencing in MCF-7 cells. Additionally, the activity of a p21 promoter reporter is
repressed following transfection with an AP-2y expression construct in HepG2 cells.
These results coupled with ChIP experiments showing AP-2y occupancy at the proximal
promoter region of p21 in cycling MCF-7 cells, implicate AP-2y in the repression of
p21 transcription and suggest a role for AP2y in- the, control of cell cycle in breast
carcinoma in part through the transcriptional repression of p21
Atmospheres of brown dwarfs
No full textChH highlights financial support of the European Community under the FP7 by an ERC starting grant. SLC acknowledges financial support of University of LeicesterBrown Dwarfs are the coolest class of stellar objects known to date. Our present perception is that Brown Dwarfs follow the principles of star formation, and that Brown Dwarfs share many characteristics with planets. Being the darkest and lowest mass stars known makes Brown Dwarfs also the coolest stars known. This has profound implication for their spectral fingerprints. Brown Dwarfs cover a range of effective temperatures which cause brown dwarfs atmospheres to be a sequence that gradually changes from a M-dwarf-like spectrum into a planet-like spectrum. This further implies that below an effective temperature of ≲ 2800K, clouds form already in atmospheres of objects marking the boundary between M-Dwarfs and brown dwarfs. Recent developments have sparked the interest in plasma processes in such very cool atmospheres: sporadic and quiescent radio emission has been observed in combination with decaying Xray-activity indicators across the fully convective boundary.Peer reviewe
Recruitment of AP-1 clathrin adaptors to liposomal membranes
No full textProtein and membrane traffic between organelles within the endocytic and exocytic pathway is mediated most prominently by coated vesicles. These vesicles are formed by the assembly of cytosolic coat proteins onto the donor membrane, which deform it into a bud so that vesicles can pinch off. Clathrin with its associated adaptors, COPI and COPII are the three major coats. Various in vitro studies allowed insight into the mechanism of coat formation. COPI and COPII vesicle budding from chemically defined liposomes has been reconstituted in vitro, using pure coat compounds. Further, it has been demonstrated that cargo is sorted into these vesicles. The mechanism of clathrin-coated vesicle formation appears to be more complicated. The AP-1 clathrin adaptor is involved in vesicle formation at the transGolgi network and endosomes. This work presents an in vitro assay where AP-1 is recruited to peptidoliposomes, presenting covalently linked peptides corresponding to sorting signals. In this system, AP-1 recruitment depends on myristyolated ADP-ribosylation factor(ARF1), GTP or GMP-PNP, tyrosine signals and a small amount of phosphoinositides, most prominently phosphatidyl inositol 4,5bisphosphate. In such a minimal system AP-1 is recruited as a highmolecular weight complex indicating the formation of a precoat in the absence of clathrin. GTP hydrolysis, induced by ARF GTPase-activating protein(ARFGAP1), disassembled this complex. Further, AP-1 is able to enhance the GAP activity of ARFGAP1 on myristoylated ARF1, suggesting a regulatory function of GTP hydrolysis in early steps of coat recruitment. This work provides insights into the mechanism of AP-1 clathrin coat formation which might also be used to investigate the recruitment of other coats
ISC/OSI Journal Authors Survey Report
No full textOn behalf of the Joint Information Systems Committee (JISC) and the Open Society Institute (OSI) a survey of journal authors has been carried out by Key Perspectives Ltd. The terms of reference were to poll a cohort of authors who had published on an open access basis and another cohort of authors who had published their work in conventional journals without making the article available on open access. The survey’s aims were to investigate the authors’ awareness of new open access possibilities, the ease of identification of and submission to open access outlets, their experiences of publishing their work in this way, their concerns about any implications open access publishing may have upon their careers, and the reasons why (or not) they chose to publish through an open access outlet
Characterizing the role of p21-Activated Kinase 3 (PAK3) in AP-1-induced transformation
No full textIncludes bibliographical references.Previous studies identified p21-Activated Kinase 3 (PAK3), a serine/threonine kinase, as a potential AP-1 target gene. PAK3 has been implicated in a variety of pathological disorders and over-expression of other PAK-family members has been linked to cancer. In this study, we investigated AP-1 regulation of PAK3 expression and the role of PAK3 in cJun/AP-1-associated cellular transformation. Our results showed elevated PAK3 expression at both the mRNA and protein level in cJun-over-expressing Rat1a fibroblasts, as well as in transformed human fibroblasts. Elevated PAK3 protein levels were also seen in cervical, ovarian, oesophageal and breast cancer cells lines, while poor survival tracked with high PAK3 expression in ovarian cancer patient material. Elevated PAK3 levels appear to play no role in the proliferation of transformed or cancerous cells, however appears vital for the transformed morphology and actin distribution. These cytoskeletal changes seem to be the underlying force governing cellular migration, as inhibition of PAK3 significantly reduced the motility of both transformed fibroblasts and cancer cell lines. Our data shows that elevated PAK3 expression in response to AP-1 over-expression is regulated through the transcriptional activation of the PAK3 promoter by AP-1 binding directly to a single site in the promoter. We also show that constitutive activation of PAK3 results in changes in cJun phosphorylation and an increase in AP-1 activity, which can be inhibited by a serine/threonine kinase inhibitor. PAK3 and AP-1 proteins were also shown to directly interact with each other. Our study is a first to describe a role for AP-1 in regulating PAK3 expression, and PAK3 in regulating AP-1 activity, identifying a potential feedback loop in which PAK3 is an AP-1 target required for cytoskeletal reorganization and migration observed in transformed cells
Communicating Chemical Congregation: A Molecular AND Logic Gate with Three Chemical Inputs as a �Lab-on-a-Molecule� Prototype
No full textPT: J; CR: ABBOTT EA, 1950, FLATLAND ROMANCE MAN AMENDOLA V, 2001, ACCOUNTS CHEM RES, V34, P488 BADJIC JD, 2004, SCIENCE, V303, P1845 BAG B, 2005, CHEM COMMUN 0128, P513 BALZANI V, 2003, MOL DEVICES MACHINES BHATTACHARYA S, 2003, CHEM COMMUN, P1158 BISSELL RA, 1992, J CHEM SOC P2, P1559 CALLAN JF, 2004, CHEM COMMUN, P2048 CHANG CJ, 2004, CHEM BIOL, V11, P203 DESILVA AP, 1993, NATURE, V364, P42 DESILVA AP, 1997, CHEM REV, V97, P1515 DESILVA AP, 1997, J AM CHEM SOC, V119, P7891 DESILVA AP, 1999, J AM CHEM SOC, V121, P1393 DESILVA AP, 2001, ELECT TRANSFER CHEM, V5, P156 DESILVA AP, 2001, MOL SWITCHES, P339 DESILVA AP, 2004, CHEM-EUR J, V10, P574 DESILVA SA, 2002, CHEM COMMUN, P1360 FABBRIZZI L, 1999, ACCOUNTS CHEM RES, V32, P846 FARINAS J, 1999, J BIOL CHEM, V274, P7603 GUNNLAUGSSON T, 2003, ORG BIOMOL CHEM, V1, P3265 GUNNLAUGSSON T, 2003, ORG LETT, V5, P4065 GUNNLAUGSSON T, 2004, TETRAHEDRON, V60, P11239 GUO XF, 2004, ADV MATER, V16, P125 HE HR, 2003, ANAL CHEM, V75, P549 HE HR, 2003, J AM CHEM SOC, V125, P1468 HERNANDEZ JV, 2004, SCIENCE, V306, P1532 HIRSCH ED, 2002, NEW DICT CULTURAL LI IZATT RM, 1976, J AM CHEM SOC, V98, P7626 IZATT RM, 1985, CHEM REV, V85, P271 KOSKELA SJM, 2004, CHEM COMMUN, P945 LANKSHEAR MD, 2006, CHEM COMMUN 0214, P612 LIM NC, 2004, CHEM COMMUN 0507, P1094 MARGULIES D, 2004, J AM CHEM SOC, V126, P15400 MARGULIES D, 2005, NAT MATER, V4, P768 MILLMAN J, 1988, MICROELECTRONICS NICOLL D, 2004, DIAGNOSTIC TESTS RAYMO FM, 2002, ADV MATER, V14, P401 SAUVAGE JP, 1998, ACCOUNTS CHEM RES, V31, P611 SMITH RM, 1974, CRITICAL STABILITY C STOJANOVIC MN, 2003, NAT BIOTECHNOL, V21, P1069 TSIEN RY, 1992, AM J PHYSIOL, V263, C723 TUSA JK, 2005, J MATER CHEM, V15, P2640 UCHIYAMA S, 2004, J AM CHEM SOC, V126, P3032 UCHIYAMA S, 2005, J AM CHEM SOC, V127, P8920 WANG HM, 2004, CHEM COMMUN 0321, P670 WISKUR SL, 2001, ACCOUNTS CHEM RES, V34, P963 WOODROOFE CC, 2003, J AM CHEM SOC, V125, P11458; NR: 47; TC: 10; J9: J AM CHEM SOC; PG: 2; GA: 034GNSource type: Electronic(1
The Treatment of Ties in AP Correlation
No full textThe Kendall tau and AP correlation coefficients are very commonly use to compare two rankings over the same set of items. Even though Kendall tau was originally defined assuming that there are no ties in the rankings, two alternative versions were soon developed to account for ties in two different scenarios: measure the accuracy of an observer with respect to a true and objective ranking, and measure the agreement between two observers in the absence of a true ranking. These two variants prove useful in cases where ties are possible in either ranking, and may indeed result in very different scores. AP correlation was devised to incorporate a top-heaviness component into Kendall tau, penalizing more heavily if differences occur between items at the top of the rankings, making it a very compelling coefficient in Information Retrieval settings. However, the treatment of ties in AP correlation remains an open problem. In this paper we fill this gap, providing closed analytical formulations of AP correlation under the two scenarios of ties contemplated in Kendall tau. In addition,we developed an R package that implements these coefficients.Best Short Paper Accepted author manuscriptMultimedia ComputingWeb Information System
Blockade of AP-1 potentiates endocrine therapy and overcomes resistance
No full textUnlabelledThe transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program.ImplicationsAP-1 represents a viable therapeutic target to overcome endocrine resistance. Mol Cancer Res; 14(5); 470-81. ©2016 AACR
Brown, Black and White
No full textEdition of 20, 9 TI (CD), BAT, 3 AP (CD), 2 TP, CP (Tcs)Rives BFK(1) brown (2) blac
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