Pirin delocalization in melanoma progression identified by high content immuno-detection based approaches

Licciulli, Silvia; Luise, Chiara; Zanardi, Andrea; Giorgetti, Luca; Viale, Giuseppe; Lanfrancone, Luisa; Carbone, Roberta; Alcalay, Myriam

doi:10.1186/1471-2121-11-5

Cited by 30 publications

(35 citation statements)

References 20 publications

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“…However, PRN proteins have functions also in other locations in addition to the nucleus. Notably, human PRN has been shown to dislocate in melanomas from the nucleus to the cytoplasm, where it seems to play a role in melanoma progression (Licciulli et al ., 2010). In Arabidopsis, PRN1 is involved in ABA responses during germination and early seedling growth, possibly through the proven interaction with the plasma membrane-localized Gα subunit (Lapik and Kaufman, 2003).…”

Section: Discussionmentioning

confidence: 99%

PIRIN2 stabilizes cysteine proteaseXCP2 and increases susceptibility to the vascular pathogenRalstonia solanacearumin Arabidopsis

et al. 2014

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PIRIN (PRN) is a member of the functionally diverse cupin protein superfamily. There are four members of the Arabidopsis thaliana PRN family, but the roles of these proteins are largely unknown. Here we describe a function of the Arabidopsis PIRIN2 (PRN2) that is related to susceptibility to the bacterial plant pathogen Ralstonia solanacearum. Two prn2 mutant alleles displayed decreased disease development and bacterial growth in response to R. solanacearum infection. We elucidated the underlying molecular mechanism by analyzing PRN2 interactions with the papain-like cysteine proteases (PLCPs) XCP2, RD21A, and RD21B, all of which bound to PRN2 in yeast two-hybrid assays and in Arabidopsis protoplast co-immunoprecipitation assays. We show that XCP2 is stabilized by PRN2 through inhibition of its autolysis on the basis of PLCP activity profiling assays and enzymatic assays with recombinant protein. The stabilization of XCP2 by PRN2 was also confirmed in planta. Like prn2 mutants, an xcp2 single knockout mutant and xcp2 prn2 double knockout mutant displayed decreased susceptibility to R. solanacearum, suggesting that stabilization of XCP2 by PRN2 underlies susceptibility to R. solanacearum in Arabidopsis.

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Section: Discussionmentioning

confidence: 99%

PIRIN2 stabilizes cysteine proteaseXCP2 and increases susceptibility to the vascular pathogenRalstonia solanacearumin Arabidopsis

et al. 2014

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“…PIR may contribute to this phenotype by modulating the transcription of key regulators of senescence, but it may also exert its function through other mechanisms. A detailed analysis of PIR subcellular localization in melanoma revealed that advanced stage melanomas display increasing amounts of cytoplasmic PIR, 27 suggesting the existence of additional functions that could confer yet unknown characteristics to tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, PIR subcellular localization differed among samples: the protein was nuclear in melanocytes, but melanoma samples displayed growing amounts of cytoplasmic protein at advanced stages. 27 PIR mRNA expression levels in eight primary melanoma cell lines and nine metastatic melanoma cell lines were next investigated by qRT-PCR and compared with those in normal melanocytes from primary cultures. GAPDH expression was used to normalize expression levels among samples.…”

Section: Analysis Of Pir Expression In Human Adult Tissuesmentioning

confidence: 99%

Pirin Inhibits Cellular Senescence in Melanocytic Cells

Licciulli

Luise

Scafetta

et al. 2011

The American Journal of Pathology

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Cellular senescence has been widely recognized as a tumor suppressing mechanism that acts as a barrier to cancer development after oncogenic stimuli. A prominent in vivo model of the senescence barrier is represented by nevi, which are composed of melanocytes that, after an initial phase of proliferation induced by activated oncogenes (most commonly BRAF), are blocked in a state of cellular senescence. Transformation to melanoma occurs when genes involved in controlling senescence are mutated or silenced and cells reacquire the capacity to proliferate. Pirin (PIR) is a highly conserved nuclear protein that likely functions as a transcriptional regulator whose expression levels are altered in different types of tumors. We analyzed the expression pattern of PIR in adult human tissues and found that it is expressed in melanocytes and has a complex pattern of regulation in nevi and melanoma: it is rarely detected in mature nevi, but is expressed at high levels in a subset of melanomas. Loss of function and overexpression experiments in normal and transformed melanocytic cells revealed that PIR is involved in the negative control of cellular senescence and that its expression is necessary to overcome the senescence barrier. Our results suggest that PIR may have a relevant role in melanoma progression.

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“…As seen in Table 2, our measures p and P V reported the intervention capabilities of Pirin, STC2, SNCA, and WNT5A. STC2 is known to interact with MMP-3, 41 another variable in this network, SNCA is known to be aberrantly hypermethylated in human cancer cells, 42 it is known that "cytoplasmic localization of PIR may represent a characteristic of WNT5A network for melanoma progression", 43 and WNT5A has a known role in human melanoma progression. 37 That three of our top four intervention targets are either melanoma-related or cancer-related speaks well for their true intervention capabilities.…”

Section: B2mentioning

confidence: 94%

Identifying Targets for Intervention by Analyzing Basins of Attraction

Verdicchio¹,

S²

2010

Biocomputing 2011

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Motivation:A grand challenge in the modeling of biological systems is the identification of key variables which can act as targets for intervention. Good intervention targets are the "key players" in a system and have significant influence over other variables; in other words, in the context of diseases such as cancer, targeting these variables with treatments and interventions will provide the greatest effects because of their direct and indirect control over other parts of the system. Boolean networks are among the simplest of models, yet they have been shown to adequately model many of the complex dynamics of biological systems. Often ignored in the Boolean network model, however, are the so called basins of attraction. As the attractor states alone have been shown to correspond to cellular phenotypes, it is logical to ask which variables are most responsible for triggering a path through a basin to a particular attractor.Results: This work claims that logic minimization (i.e. classical circuit design) of the collections of states in Boolean network basins of attraction reveals key players in the network. Furthermore, we claim that the key players identified by this method are often excellent targets for intervention given a network modeling a biological system, and more importantly, that the key players identified are not apparent from the attractor states alone, from existing Boolean network measures, or from other network measurements. We demonstrate these claims with a well-studied yeast cell cycle network and with a WNT5A network for melanoma, computationally predicted from gene expression data.

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Pirin delocalization in melanoma progression identified by high content immuno-detection based approaches

Cited by 30 publications

References 20 publications

PIRIN2 stabilizes cysteine proteaseXCP2 and increases susceptibility to the vascular pathogenRalstonia solanacearumin Arabidopsis

PIRIN2 stabilizes cysteine proteaseXCP2 and increases susceptibility to the vascular pathogenRalstonia solanacearumin Arabidopsis

Pirin Inhibits Cellular Senescence in Melanocytic Cells

Identifying Targets for Intervention by Analyzing Basins of Attraction

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