Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0282612 (PIN)
 2,291 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dual inactivation of PTEN and INK4a/ARF tumor suppressor genes is a common feature observed in a broad spectrum of human cancer types. To validate functional collaboration between these genes in tumor suppression, we examined the biological consequences of Pten and/or Ink4a/Arf deficiency in cells and mice. Relative to single mutant controls, Ink4a/Arf-/-Pten+/- mouse embryonic fibroblast cultures exhibited faster rates of growth in reduced serum, grew to higher saturation densities, produced more colonies upon low density seeding, and showed increased susceptibility to transformation by oncogenic H-Ras. Ink4a/Arf deficiency reduced tumor-free survival and shortened the latency of neoplasias associated with Pten heterozygosity, specifically pheochromocytoma, prostatic intraepithelial neoplasia, and endometrial hyperplasia. Compound mutant mice also exhibited an expanded spectrum of tumor types including melanoma and squamous cell carcinoma. Functional synergy between Ink4a/Arf and Pten manifested most prominently in the development of pheochromocytoma, prompting an analysis of genes and loci implicated in this rare human neoplasm. The classical pheochromocytoma genes Ret, Vhl, and Nf-1 remained intact, a finding consistent with the intersection of these genes with pathways engaged by Pten and Ink4a/Arf. Notably, conventional and array-comparative genomic hybridization revealed frequent loss of distal mouse chromosome 4 in a region syntenic to human chromosome 1p that is implicated in human pheochromocytoma. This study provides genetic evidence of collaboration between Pten and Ink4a/Arf in constraining the growth and oncogenic transformation of cultured cells and in suppressing a wide spectrum of tumors in vivo.
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PMID:Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice. 1181 30

Plant development is characterized by a profound ability to regenerate and form tissues with new axes of polarity. An unsolved question concerns how the position within a tissue and cues from neighboring cells are integrated to specify the polarity of individual cells. The canalization hypothesis proposes a feedback effect of the phytohormone auxin on the directionality of intercellular auxin flow as a means to polarize tissues. Here we identify a cellular and molecular mechanism for canalization. Local auxin application, wounding, or auxin accumulation during de novo organ formation lead to rearrangements in the subcellular polar localization of PIN auxin transport components. This auxin effect on PIN polarity is cell-specific, does not depend on PIN transcription, and involves the Aux/IAA-ARF (indole-3-acetic acid-auxin response factor) signaling pathway. Our data suggest that auxin acts as polarizing cue, which links individual cell polarity with tissue and organ polarity through control of PIN polar targeting. This feedback regulation provides a conceptual framework for polarization during multiple regenerative and patterning processes in plants.
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PMID:Canalization of auxin flow by Aux/IAA-ARF-dependent feedback regulation of PIN polarity. 1704 14

The directional flow of the plant hormone auxin mediates multiple developmental processes, including patterning and tropisms. Apical and basal plasma membrane localization of AUXIN-RESISTANT1 (AUX1) and PIN-FORMED1 (PIN1) auxin transport components underpins the directionality of intercellular auxin flow in Arabidopsis thaliana roots. Here, we examined the mechanism of polar trafficking of AUX1. Real-time live cell analysis along with subcellular markers revealed that AUX1 resides at the apical plasma membrane of protophloem cells and at highly dynamic subpopulations of Golgi apparatus and endosomes in all cell types. Plasma membrane and intracellular pools of AUX1 are interconnected by actin-dependent constitutive trafficking, which is not sensitive to the vesicle trafficking inhibitor brefeldin A. AUX1 subcellular dynamics are not influenced by the auxin influx inhibitor NOA but are blocked by the auxin efflux inhibitors TIBA and PBA. Furthermore, auxin transport inhibitors and interference with the sterol composition of membranes disrupt polar AUX1 distribution at the plasma membrane. Compared with PIN1 trafficking, AUX1 dynamics display different sensitivities to trafficking inhibitors and are independent of the endosomal trafficking regulator ARF GEF GNOM. Hence, AUX1 uses a novel trafficking pathway in plants that is distinct from PIN trafficking, providing an additional mechanism for the fine regulation of auxin transport.
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PMID:Subcellular trafficking of the Arabidopsis auxin influx carrier AUX1 uses a novel pathway distinct from PIN1. 1711 55

Cell polarity manifested by the polar cargo delivery to different plasma-membrane domains is a fundamental feature of multicellular organisms. Pathways for polar delivery have been identified in animals; prominent among them is transcytosis, which involves cargo movement between different sides of the cell [1]. PIN transporters are prominent polar cargoes in plants, whose polar subcellular localization determines the directional flow of the signaling molecule auxin [2, 3]. In this study, we address the cellular mechanisms of PIN polar targeting and dynamic polarity changes. We show that apical and basal PIN targeting pathways are interconnected but molecularly distinct by means of ARF GEF vesicle-trafficking regulators. Pharmacological or genetic interference with the Arabidopsis ARF GEF GNOM leads specifically to apicalization of basal cargoes such as PIN1. We visualize the translocation of PIN proteins between the opposite sides of polarized cells in vivo and show that this PIN transcytosis occurs by endocytic recycling and alternative recruitment of the same cargo molecules by apical and basal targeting machineries. Our data suggest that an ARF GEF-dependent transcytosis-like mechanism is operational in plants and provides a plausible mechanism to trigger changes in PIN polarity and hence auxin fluxes during embryogenesis and organogenesis.
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PMID:ARF GEF-dependent transcytosis and polar delivery of PIN auxin carriers in Arabidopsis. 1839 92

We report here that the polycomb group protein Bmi1 promotes prostate tumorigenesis. Bmi1 is detected at higher levels in androgen-independent PC3 and DU145 than in androgen-dependent LNCaP prostate cancer (CaP) cells. Ectopic Bmi1 enhanced the expression of human telomerase reverse transcriptase (hTERT) and suppressed the exression of p16(INK4A) and p14(ARF) in CaP cells. Consistent with these observations, immunohistochemical staining of 51 cases of primary CaP specimens revealed 1.4 fold (p=0.014) and 1.3 fold (p=0.051) higher levels of Bmi1-positive cells in carcinoma compared to normal prostatic epithelial cells and PIN, respectively. In primary CaPs, Bmi1 expression was associated with a reduction in p16(INK4A) and p14(ARF). Furthermore, in comparison to empty vector-transfected cells, Bmi1-expressing DU145 cells formed significantly larger tumors in NOD/SCID mice. Taken together, we demonstrate that Bmi1 promotes prostate tumorigenesis.
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PMID:Bmi1 promotes prostate tumorigenesis via inhibiting p16(INK4A) and p14(ARF) expression. 1881 67

The polar, sub-cellular localization of PIN auxin efflux carriers determines the direction of intercellular auxin flow, thus defining the spatial aspect of auxin signalling. Dynamic, transcytosis-like relocalizations of PIN proteins occur in response to external and internal signals, integrating these signals into changes in auxin distribution. Here, we examine the cellular and molecular mechanisms of polar PIN delivery and transcytosis. The mechanisms of the ARF-GEF-dependent polar targeting and transcytosis are well conserved and show little variations among diverse Arabidopsis ecotypes consistent with their fundamental importance in regulating plant development. At the cellular level, we refine previous findings on the role of the actin cytoskeleton in apical and basal PIN targeting, and identify a previously unknown role for microtubules, specifically in basal targeting. PIN protein delivery to different sides of the cell is mediated by ARF-dependent trafficking with a previously unknown complex level of distinct ARF-GEF vesicle trafficking regulators. Our data suggest that alternative recruitment of PIN proteins by these distinct pathways can account for cell type- and cargo-specific aspects of polar targeting, as well as for polarity changes in response to different signals. The resulting dynamic PIN positioning to different sides of cells defines a three-dimensional pattern of auxin fluxes within plant tissues.
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PMID:Cellular and molecular requirements for polar PIN targeting and transcytosis in plants. 1982 3

Auxin efflux carrier PIN proteins have been intensively investigated as they are the first polar cargos to be identified in plants with a direct relevance for plant patterning. Based on their polar localization; PIN proteins direct the intercellular flow of signaling molecule auxin and thus bear a rate limiting effect on the formation of auxin activity gradients. With this influence on directionality and extent of auxin transport PINs play crucial roles in plant body organization. Many factors such as vesicle trafficking regulator ARF-GEF GNOM, a kinase PINOID, a retromer complex and membrane sterol composition influence polar PIN localization. Recent work uncovers the mechanism that generates default PIN polarity. Real time PIN tracking reveals that PIN polarity is generated from initially non-polar secretion via endocytosis and subsequent polar recycling. In addition, the Rab5 endocytic pathway emerges to be important for polar PIN localization as Rab5 interference causes non-polar distribution of PINs. This non-polar distribution of PINs during embryogenesis transiently alters auxin activity gradients and changes organ identity by transforming embryonic leaf cells to root fates. These findings for the first time link PIN polarity-based auxin activity gradient to cell fate decisions and thus demonstrate morphogen (a substance influencing cell fates on its concentration gradient) characters of auxin. They also suggest an auxin activity distribution-dependent sensing module that executes differential apical and basal developmental program during plant embryogenesis.
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PMID:Cell polarity in plants: Linking PIN polarity generation mechanisms to morphogenic auxin gradients. 2083 91

Auxin is an essential plant-specific regulator of patterning processes that also controls directional growth of roots and shoots. In response to gravity stimulation, the PIN3 auxin transporter polarizes to the bottom side of gravity-sensing root cells, presumably redirecting the auxin flux toward the lower side of the root and triggering gravitropic bending. By combining live-cell imaging techniques with pharmacological and genetic approaches, we demonstrate that PIN3 polarization does not require secretion of de novo synthesized proteins or protein degradation, but instead involves rapid, transient stimulation of PIN endocytosis, presumably via a clathrin-dependent pathway. Moreover, gravity-induced PIN3 polarization requires the activity of the guanine nucleotide exchange factors for ARF GTPases (ARF-GEF) GNOM-dependent polar-targeting pathways and might involve endosome-based PIN3 translocation from one cell side to another. Our data suggest that gravity perception acts at several instances of PIN3 trafficking, ultimately leading to the polarization of PIN3, which presumably aligns auxin fluxes with gravity vector and mediates downstream root gravitropic response.
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PMID:Gravity-induced PIN transcytosis for polarization of auxin fluxes in gravity-sensing root cells. 2113 43

Phototropism is an adaptation response, through which plants grow towards the light. It involves light perception and asymmetric distribution of the plant hormone auxin. Here we identify a crucial part of the mechanism for phototropism, revealing how light perception initiates auxin redistribution that leads to directional growth. We show that light polarizes the cellular localization of the auxin efflux carrier PIN3 in hypocotyl endodermis cells, resulting in changes in auxin distribution and differential growth. In the dark, high expression and activity of the PINOID (PID) kinase correlates with apolar targeting of PIN3 to all cell sides. Following illumination, light represses PINOID transcription and PIN3 is polarized specifically to the inner cell sides by GNOM ARF GTPase GEF (guanine nucleotide exchange factor)-dependent trafficking. Thus, differential trafficking at the shaded and illuminated hypocotyl side aligns PIN3 polarity with the light direction, and presumably redirects auxin flow towards the shaded side, where auxin promotes growth, causing hypocotyls to bend towards the light. Our results imply that PID phosphorylation-dependent recruitment of PIN proteins into distinct trafficking pathways is a mechanism to polarize auxin fluxes in response to different environmental and endogenous cues.
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PMID:Light-mediated polarization of the PIN3 auxin transporter for the phototropic response in Arabidopsis. 2146 Aug 6

The analysis of cell polarity in plants is fueled by the discovery and analysis of auxin efflux carrier PIN proteins that show polar localizations in various plant cell types in line with their roles in directional cell to cell auxin transport. As this asymmetry in cellular PIN localization drives directional auxin fluxes, abnormalities in PIN localizations modify auxin transport culminating into range of auxin distribution defective phenotypes. Because of this influence of PIN localization on plant development via changes in auxin distribution, mechanisms establishing, maintaining and altering PIN polarity are of intense interest in the plant field during the recent years. Recent findings suggest that two categories of molecules, namely AGC-3 kinase family members PINOID, WAG1, WAG2 and ARF-GEF family member GNOM predominantly influence the polar localization of PINs. The emerging mechanism for AGC-3 kinases and ARF-GEF action suggest that AGC-3 kinases predominantly phosphorylate PINs at the plasma membrane for eventual PIN internalization and PIN sorting into ARF-GEF GNOM independent polar recycling pathways. In case of mutant for AGC-3 kinases or mutations in AGC-3 kinase-targeted PIN residues, much less phosphorylated PINs are recruited into ARFGEF GNOM-dependent polar recycling pathway. When ARF-GEF GNOM is inactive, the bias is shifted for rerouting less efficiently phosphorylated PINs into GNOM-independent polar recycling pathways that generally prefer efficiently phosphorylated PINs. Thus, balance shifts between the extent of AGC-3 kinase mediated PIN phosphorylation and the functioning of ARFGEF instruct PIN polarity establishment and/or PIN polarity alterations. Recent studies report utilization of this AGC-3 kinase and ARF-GEF PIN polarity regulation module during diverse developmental and response programs including shoot patterning, root growth, phototropism, gravitropism, organogenesis, leaf epidermal cell indentations and fruit valve margin formation. Based on these findings the same theme of phosphorylated PIN sorting into differential polar recycling pathways for PIN polarity establishment and alteration seems to be employed in a context-dependent manner.
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PMID:PIN polarity regulation by AGC-3 kinases and ARF-GEF: a recurrent theme with context dependent modifications for plant development and response. 2185 55


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