A small-molecule inhibitor shows that pirin regulates migration of melanoma cells

Miyazaki, Isao; Simizu, Siro; Okumura, Hideo; Takagi, Satoshi; Osada, Hiroyuki

doi:10.1038/nchembio.423

Cited by 100 publications

(113 citation statements)

References 48 publications

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“…The single human PRN has been shown to interact with the nuclear factor I/CCAAT box transcription factor (Wendler et al ., 1997) and the oncoprotein Bcl-3 (Dechend et al ., 1999). It has been implicated in several processes, including transcriptional control, apoptosis, migration and cellular senescence of melanoma cells (Courtois and Gilmore, 2006; Ahmed and Milner, 2009; Miyazaki et al ., 2010; Licciulli et al ., 2011). Plants normally have small complements of PRN genes, most of which have poorly understood roles.…”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…A recent report shows that PIR controls melanoma cell migration through the transcriptional regulation of snail homolog 2, SNAI2 (previously SLUG). 16 Other reports described quercetinase enzymatic activity, 17 and regulation of apoptosis 18,19 and stress response, unveiling a high degree of cell-type and species specificity in PIR function.…”

mentioning

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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“…Pirin has additionally been linked to the metastasis of melanoma cells (22,23). It has been shown that pirin expression is significantly up-regulated in the spleen and kidney of cytosolic superoxide dismutase (SOD)-deficient mice (24).…”

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Pirin is an iron-dependent redox regulator of NF-κB

Liu

Rehmani²,

Esaki³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

146

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Pirin is a nuclear nonheme Fe protein of unknown function present in all human tissues. Here we describe that pirin may act as a redox sensor for the nuclear factor κB (NF-κB) transcription factor, a critical mediator of intracellular signaling that has been linked to cellular responses to proinflammatory signals and controls the expression of a vast array of genes involved in immune and stress responses. Pirin's regulatory effect was tested with several metals and at different oxidations states, and our spectroscopic results show that only the ferric form of pirin substantially facilitates binding of NF-κB proteins to target κB genes, a finding that suggests that pirin performs a redox-sensing role in NF-κB regulation. The molecular mechanism of such a metal identity-and redox state-dependent regulation is revealed by our structural studies of pirin. The ferrous and ferric pirin proteins differ only by one electron, yet they have distinct conformations. The Fe center is shown to play an allosteric role on an R-shaped surface area that has two distinct conformations based on the identity and the formal redox state of the metal. We show that the R-shaped area composes the interface for pirin-NF-κB binding that is responsible for modulation of NF-κB's DNAbinding properties. The nonheme Fe protein pirin is proposed to serve as a reversible functional switch that enables NF-κB to respond to changes in the redox levels of the cell nucleus.metalloprotein | coregulator | reactive oxygen species (ROS) | oxidative stress | signal transduction activation

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A small-molecule inhibitor shows that pirin regulates migration of melanoma cells

Cited by 100 publications

References 48 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

Pirin is an iron-dependent redox regulator of NF-κB

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