Search

Migraine is a complex disabling condition which is associated with dysregulation of several pathways particularly those being associated with immune responses. In order to assess contribution of protein inhibitor of activated STAT (PIAS) in the pathogenesis of migraine, we quantified expression levels of PIAS1–PIAS4 genes in the circulation of patients with migraine compared with controls. Expression of PIAS1 was substantially lower in total migraineurs compared with controls (ratio of mean expressions (RME) = 0.18, SE = 0.29, P value < 0.001) and in both male and female migraineurs compared with sex-matched controls. Expression of PIAS2 was lower in migraineurs without aura compared with controls (RME = 0.64, SE = 0.31, P value = 0.04) and in male subgroup of these patients compared with male controls (RME = 0.60, SE = 0.22, P value < 0.001). In migraineurs with aura, downregulation of PIAS2 was only observed among male subgroups (RME = 0.37, SE = 0.49, P value = 0.01). PIAS3 was downregulated in total male migraineurs (RME = 0.52, SE = 0.43, P value = 0.04) and in male migraineurs with aura (RME = 0.49, SE = 0.45, P value = 0.03) compared with male controls. Finally, PIAS4 was upregulated in total migraineurs (RME = 3.78, SE = 0. 34, P value < 0.001), female migraineurs (RME = 5.26, SE = 0.36, P value < 0.001), migraineurs with aura (RME = 4.24, SE = 0.42, P value < 0.001), female migraineurs with aura (RME = 6.13, SE = 0.47, P value < 0.001), migraineurs without aura (RME = 3.33, SE = 0.38, P value < 0.001), and female migraineurs without aura (RME = 4.47, SE = 0.41, P value < 0.001) compared with the corresponding controls. The present study suggests contribution of PIAS genes in the pathogenesis of migraine and warrants future studies to clarify the functional routes of their contribution. [ABSTRACT FROM AUTHOR]

Protein inhibitors of activated STAT (PIAS) are involved in the regulation of the JAK/STAT signaling pathway and have interactions with NF-κB, p73 and p53. These proteins regulate immune responses; therefore dysregulation in their expression leads to several immune-mediated disorders. In the present study, we examined expression of PIAS1 - 4 in peripheral blood of patients with acute/chronic inflammatory demyelinating polyradiculoneuropathy (AIDP/CIDP) compared with healthy subjects. We demonstrated down-regulation of all PIAS genes in both AIDP and CIDP cases compared with controls. Similarly, comparisons in gender-based groups revealed down-regulation of these gene0s in patients of each gender compared with gender-matched controls. There was no significant difference in expression of PIAS genes between AIDP and CIDP cases. Based on the area under the receiver operating characteristic curves, PIAS1 - 4 genes could distinguish between inflammatory demyelinating polyradiculoneuropathy and healthy status with accuracy values of 0.87, 0.87, 0.79 and 0.80, respectively. In differentiation between AIDP cases and healthy controls, these values were 0.92, 0.92, 0.83 and 0.86, respectively. Finally, PIAS1 - 4 genes could discriminate CIDP from healthy status with accuracy values of 0.82, 0.83, 0.75 and 0.75, respectively. The current study underscores the role of PIAS genes in the pathogenesis of inflammatory demyelinating polyradiculoneuropathy and their potential usage as biomarkers. [ABSTRACT FROM AUTHOR]

Aim: Protein inhibitor of activated STAT (PIAS) family includes transcriptional regulator proteins with SUMO E3 ligase activity. They regulate expression of several genes involved in cell proliferation, differentiation and survival. Method: We evaluated expression of PIAS1–4 genes in 54 breast cancer tissues and their paired adjacent noncancerous tissues. Results:PIAS2 and PIAS3 genes were significantly downregulated in tumoral tissues compared with adjacent noncancerous tissues. PIAS1–3 expressions were significantly lower in estrogen receptor (ER+) samples compared with ER- samples while PIAS4 had the opposite trend. PIAS3 expression was significantly higher in grade 1 samples compared with grade 2 samples. Conclusion: These findings highlight the role of PIAS genes in the pathogenesis of breast cancer and their association with determinants of response to antihormone therapies. [ABSTRACT FROM AUTHOR]

The protein inhibitor of activated STAT (PIAS) protein family participates in regulation of pathways triggered by cytokines. On the other hand, recent data point to the role of immune dysregulation in the pathogenesis of autism spectrum disorder (ASD). In the present study, we evaluated expression of PIAS genes in peripheral blood of 30 Iranian ASD patients and 41 age-and gender-matched normal subjects by means of quantitative real time PCR. PIASx expression was significantly correlated with age in ASD patients but not healthy subjects. No significant difference was found in expression of PIAS genes between cases and controls. Spearman correlation analysis showed significant correlations between PIAS transcript levels in nearly all study subgroups. However, PIAS1 transcript levels were not correlated with those of PIAS3 and PIASy in male subjects. Moreover, PIAS1 expression was not correlated with expression of PIASx and PIASy in ASD patients in spite of significant correlation in healthy subjects. The results of current study indicate a context-dependent interactive network between PIAS genes and warrant future studies to elaborate the role of these genes in ASD. [ABSTRACT FROM AUTHOR]

The human telomeric protein TRF2 protects chromosome ends by facilitating their organization into the protective capping structure. Here we show that the stability of TRF2 is regulated via modification by the small ubiquitin-like modifiers (SUMO). TRF2 specifically interacts with and is sumoylated by PIAS1 in mammalian cells. The proteasome inhibitor stabilizes SUMO-conjugated TRF2 without affecting the level of unmodified TRF2, suggesting that SUMO conjugation is required for proteasomal degradation of TRF2. We also show that RNF4, a mammalian SUMO-targeted ubiquitin ligase, interacts with TRF2 in a SUMO-dependent manner and preferentially targets SUMO-conjugated TRF2 for ubiquitination. Collectively, our data demonstrate that the PIAS1-mediated sumoylation status of TRF2 serves as a molecular switch that controls the level of TRF2 at telomeres. [ABSTRACT FROM AUTHOR]

PIASy, a member of the protein inhibitor of activated STAT (PIAS) family, represses the transcriptional activity of the androgen receptor (AR). In this report, we investigate the mechanism of PIASy-mediated repression of AR. We show that AR binds to the RING-finger like domain of PIASy. PIASy contains two transcriptional repression domains, RD1 and RD2. RD1, but not RD2, is required for PIASy-mediated repression of AR. We show that the RD1 domain binds HDAC1 and HDAC2 and that HDAC activity is required for PIASy-mediated AR repression. PIAS proteins possess small ubiquitin-related modifier (SUMO) E3 ligase activity. Conjugation of SUMO-1 to AR has been implicated in the regulation of AR activity. We examine if the SUMO ligase activity of PIASy is required for PIASy to repress AR. We show that a mutant PIASy, defective in promoting sumoylation, retains the ability to repress AR transcription. In addition, mutation of all the known sumoylation acceptor sites of AR does not affect the transrepression activity of PIASy on AR. Our results suggest that PIASy may repress AR by recruiting histone deacetylases, independent of its SUMO ligase activity.Oncogene (2004) 23, 3059-3066. doi:10.1038/sj.onc.1207443 Published online 23 February 2004 [ABSTRACT FROM AUTHOR]

DJ-1 is a protein involved in multiple physiological processes, including cancer, Parkinson’s disease, and male fertility. It is unknown how DJ-1 functions in the apparently different systems. The crystal structure of DJ-1 at 1.6 A˚ resolution shows that DJ-1 is a helix-strand-helix sandwich and forms a dimer. The DJ-1 structure is similar to the members of the intracellular protease PfpI family. However, the catalytic triad of Cys–His–Glu is not strictly conserved in DJ-1, implying that DJ-1 has a different catalytic mechanism if it acts as a protease or DJ-1 serves as a regulatory protein in the physiological processes. The structure shows that Leu166 positions in the middle of a helix and thus predicts that the L166P mutation will bend the helix and impact the dimerization of DJ-1. As a result, the conformational changes may diminish the DJ-1 binding with its partner, leading to the familial Parkinson’s disease caused by the single L166P mutation. [Copyright &y& Elsevier]