RanBP2 is a nucleoporin with SUMO E3 ligase activity that functions in both nucleocytoplasmic transport and mitosis. However, the biological relevance of RanBP2 and the in vivo targets of its E3 ligase activity are unknown. Here we show that animals with low amounts of RanBP2 develop severe aneuploidy in the absence of overt transport defects. The main chromosome segregation defect in cells from these mice is anaphase-bridge formation. Topoisomerase IIalpha (Topo IIalpha), which decatenates sister centromeres prior to anaphase onset to prevent bridges, fails to accumulate at inner centromeres when RanBP2 levels are low. We find that RanBP2 sumoylates Topo IIalpha in mitosis and that this modification is required for its proper localization to inner centromeres. Furthermore, mice with low amounts of RanBP2 are highly sensitive to tumor formation. Together, these data identify RanBP2 as a chromosomal instability gene that regulates Topo IIalpha by sumoylation and suppresses tumorigenesis.
How inflammatory stimuli signal to the nucleus to restrict inflammation is poorly understood. Protein inhibitor of activated STAT1 (PIAS1), a transcriptional regulator that possesses small ubiquitin-related modifier (SUMO) E3 ligase activity, inhibits immune responses by selectively blocking the binding of NF-kappaB and STAT1 to gene promoters. We report here that PIAS1 becomes rapidly phosphorylated on Ser90 residue in response to various inflammatory stimuli. Mutational studies indicate that Ser90 phosphorylation is required for PIAS1 to repress transcription. Upon TNF treatment, wild-type PIAS1, but not the Ser90A mutant, becomes rapidly associated with the promoters of NF-kappaB target genes. Furthermore, IKKalpha, but not IKKbeta, interacts with PIAS1 in vivo and mediates PIAS1 Ser90 phosphorylation, a process that requires the SUMO ligase activity of PIAS1. Our results identify a signaling pathway in which proinflammatory stimuli activate the IKKalpha-mediated sumoylation-dependent phosphorylation of PIAS1 for the immediate repression of inflammatory gene activation.
CD4 + Foxp3 + regulatory T (T reg ) cells are important for maintaining immune tolerance. Understanding the molecular mechanism that regulates T reg differentiation will facilitate the development of effective therapeutic strategies against autoimmune diseases. We report here that the SUMO E3 ligase PIAS1 restricts the differentiation of natural T reg cells by maintaining a repressive chromatin state of the Foxp3 promoter. PIAS1 acts by binding to the Foxp3 promoter to recruit DNA methyltransferases and heterochromatin protein 1 for epigenetic modifications. Pias1 deletion caused promoter demethylation, reduced histone H3 methylation at Lys 9 , and enhanced promoter accessibility. Consistently, Pias1 −/− mice displayed an increased natural T reg cell population and were resistant to the development of experimental autoimmune encephalomyelitis. Our studies have identified an epigenetic mechanism that negatively regulates the differentiation of natural T reg cells.Naturally occurring thymus-derived regulatory T (nT reg ) cells play a critical role in the maintenance of self-tolerance and homeostasis within the immune system (1-4). The transcription factor Foxp3 controls the development and function of T reg cells (5-7). Several regulatory DNA elements within the Foxp3 locus have been suggested to modulate Foxp3 expression, including the promoter region and conserved noncoding sequences (6-9). Although the transcription factors that positively regulate Foxp3 expression are well characterized (10-13), little is known about the negative regulation of Foxp3.PIAS1 (protein inhibitor of the activated signal transducer and activator of transcription STAT1) is a SUMO E3 ligase that binds to chromatin to repress transcription (14,15). The recruitment of PIAS1 to chromatin requires it to be phosphorylated on Ser 90 . This is induced by a variety of immune regulatory stimuli, including TCR (T cell receptor) activation (16). PIAS1 was phosphorylated on Ser 90 in freshly isolated thymocytes and splenocytes (17) (Fig. 1A). There was a small increase in the percentage of thymic single-positive CD4 + or CD8 + T cells in Pias1 −/− mice, although the total T cell number was not significantly altered ( fig. S1, A and B).The frequency of both thymic and splenic CD4 + Foxp3 + nT reg cells was † To whom correspondence should be addressed. bliu@ucla.edu (B.L.); kshuai@mednet.ucla.edu (K.S.). * These authors contributed equally to this manuscript. (Fig. 1B). In addition, the number of thymic CD4 + Foxp3 + nT reg cells was also significantly increased in Pias1 −/− mice (about 135%) (Fig. 1B). However, the mean intensity of Foxp3 expression in Foxp3 + cells was not altered in Pias1 −/− cells ( fig. S1C). Moreover, Pias1 disruption had no significant effect on the in vivo proliferation or survival of T reg cells ( fig. S2).To test whether PIAS1 directly regulates the intrinsic differentiation potential of nT reg cells, bone marrow from wild-type and Pias1 −/− mice depleted of CD4 + and CD8 + T cells was transplanted into sublethall...
Epigenetic gene silencing by histone modifications and DNA methylation is essential for cancer development. The molecular mechanism that promotes selective epigenetic changes during tumorigenesis is not understood. We report here that the PIAS1 SUMO ligase is involved in the progression of breast tumorigenesis. Elevated PIAS1 expression was observed in breast tumor samples. PIAS1 knockdown in breast cancer cells reduced the subpopulation of tumor-initiating cells, and inhibited breast tumor growth in vivo. PIAS1 acts by delineating histone modifications and DNA methylation to silence the expression of a subset of clinically relevant genes, including breast cancer DNA methylation signature genes such as cyclin D2 and estrogen receptor, and breast tumor suppressor WNT5A. Our studies identify a novel epigenetic mechanism that regulates breast tumorigenesis through selective gene silencing.
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