count source_label source_id relationship target_label target_id entity_type solr_id publication_id sentences 12 SIN3B UNIPROT:O75182 inhibits UNIPROT:P01106 Protein 4a12d554-c46e-11e5-9cc6-001a4ae51246 PMC4139234 In the presence of these inhibitors, Sin3b was unable to repress Myc activity (Fig. 6A).|||The results showed that although the MycD186–203 mutant activated the luciferase reporter to a similar extent as wild-type Myc, Sin3b was unable to impair transactivation by the Myc mutant (Fig. 4B), suggesting that direct interaction was required for the repression of Myc transcriptional activity by Sin3b.|||Sin3b Antagonizes Myc Transactivation Activity Sin3b functions as a transcriptional repressor through a mechanism involving recruitment of HDACs.|||Thus, Sin3b may reduce Myc activity through two parallel pathways: the canonical Sin3b-Mxd interaction, resulting in Myc target gene repression, and the reduction of Myc levels, as shown in this work. 8 SIN3B UNIPROT:O75182 methylatesProtein FPLX:Histone:H3 ProteinFamily afa7f790-0529-11f0-bb39-0050569a791b 10.1016/j.jmb.2024.168614 Eaf3/MRG15 is a chromodomain-containing protein that binds to methylated lysine 36 of histone H3 and is part of both the NuA4/TIP60 HAT complex as well as of the Rpd3S/SIN3b HDAC complex.87Methylation of H3K36 is dependent on the phosphorylation status of the CTD of RNA Pol II, restricting H3K36 methylation on the body of active genes. 8 SIN3B UNIPROT:O75182 decreases UNIPROT:P01106 Protein 4a12d554-c46e-11e5-9cc6-001a4ae51246 PMC4139234 We showed that Sin3b decreased Myc levels, whereas Sin3b depletion augmented Myc levels.|||Myc-Sin3b interaction leads to Myc deacetylation and destabilization, and co-expression of Sin3b leads to reduced Myc levels.|||A third explanation is that Sin3b leads to reduced Myc levels. 8 UNIPROT:Q9NRG4 methylatesProtein SIN3B UNIPROT:O75182 Protein 76714672-381c-11e6-9aa8-001a4ae51247 25533488 Autoradiography confirmed that SMYD2 methylates the transcription factors SIX1 (Heanue et al., 1999) and SIX2 (Boucher et al., 2000), the transcriptional corepressor SIN3B (Ayer et al., 1995), and the RNA helicase DHX15 (Wen et al., 2008) (Figure 5A).|||Furthermore, SMYD2 cannot methylate single-point mutants of SIN3B and SIX1 in which the predicted target lysine is substituted for arginine, confirming that our motif correctly predicts methylation sites on proteins (Figure 5B). 4 SIN3B UNIPROT:O75182 activates MESH:D009361 Phenotype ff2b94a0-ab16-11e6-807f-001a4ae51247 PMC5340233 SIN3B knockdown decreased invasiveness, promoted a more epithelial-like morphology in 3D, and decreased metastatic potential.|||Here, we show that individual knockdown of SIN3A causes an increase, whereas knockdown of SIN3B causes a decrease in breast cancer invasion and metastatic potential.|||Dual knockdown of SIN3A and SIN3B decreased invasion similar to SIN3B knockdown (62%,p= 0.003).|||Stable knockdown of SIN3A significantly increased invasion (95%,p= 0.008), whereas knockdown of SIN3B significantly decreased invasion (43%,p= 0.027). 4 UNIPROT:Q75NE6 inhibits SIN3B UNIPROT:O75182 Protein 89a5cb14-3821-11e6-aaca-001a4ae51246 PMC4380620 Furthermore, miRNAs, such as miR17-92 that represses SIN3 transcription regulator family member B (Sin3b), HMG-box transcription factor 1 (Hbp1), suppressor of variegation 4-20 homolog 1 (Suv420h1), and B cell translocation gene 1 (Btg1) to regulate chromatin structure as well as the apoptosis facilitator Bim[47], are repressive mediators of Myc action. 4 UNIPROT:P35226 inhibits SIN3B UNIPROT:O75182 Protein f8914a30-8664-11f0-afc2-0050569a791b 10.1016/j.mad.2021.111432 More recently, Bmi-1 was reported to directly repress Sin3B, a chromatin-associated protein that is stimulated by oncogenic stress and is required for OIS (DiMauro et al., 2015). 4 UNIPROT:P01106 increases SIN3B UNIPROT:O75182 Protein 1bad42b0-c46b-11e5-8491-001a4ae51247 PMC4191901 First, MYC inactivation induced the protein expression of Sin3b, Hbp1, Suv420h1, Btg1, and all three Bim isoforms in control, but notmiR-17-92-expressing cells as measured by western blot analysis (Figures 4A andS4). 2 SIN3B UNIPROT:O75182 deacetylatesProtein UNIPROT:P01106 Protein 4a12d554-c46e-11e5-9cc6-001a4ae51246 PMC4139234 Sin3b Deacetylates Myc and Promotes Myc Degradation The fact that we did not find correlation between the presence of Sin3a/b and transcriptional repression by Myc in most genes led us to the hypothesis that the major effect of Sin3-HDAC binding was not at the level of transcriptional repression. 2 SIN3B UNIPROT:O75182 increases UNIPROT:P01106 Protein 4a12d554-c46e-11e5-9cc6-001a4ae51246 PMC4139234 We showed that Sin3b decreased Myc levels, whereas Sin3b depletion augmented Myc levels. 2 SIN3B UNIPROT:O75182 inhibits GO:0006351 Phenotype b0268860-3387-11e8-87fd-001a4a160176 PMC5216265 However, terminal differentiation of specific lineages is impaired uponSin3Binactivation, resulting in late-embryonic lethality ofSin3B−/−mice.15In quiescent fibroblasts and hepatocytes, Sin3B is tethered to E2F target loci and represses transcription in a HDAC-dependent manner.15-17Consistent with these biochemical properties, Sin3B is required for quiescence upon serum starvation and for cellular senescence upon oncogene activation or serial passaging in mouse embryonic fibroblasts.15,18,19These experiments indicate that Sin3B modulates cell cycle withdrawal and differentiation in somatic cells. 2 SIN3B UNIPROT:O75182 inhibits GO:0006351 Phenotype 4a12d554-c46e-11e5-9cc6-001a4ae51246 PMC4139234 The mechanism through which Sin3b represses transcription involves the recruitment of histone deacetylases (HDACs) types 1 and 2 (28–30). 2 SIN3B UNIPROT:O75182 activates GO:0007049 Phenotype 1bad42b0-c46b-11e5-8491-001a4ae51247 PMC4191901 Sin3b interacts with Hbp1 and recruits HDACs to silence proliferation-related genes and mediate cell cycle exit and senescence (David et al., 2008; Grandinetti et al., 2009; Swanson et al., 2004). 2 SIN3B UNIPROT:O75182 activates GO:0007049 Phenotype b0268860-3387-11e8-87fd-001a4a160176 PMC5216265 However, terminal differentiation of specific lineages is impaired uponSin3Binactivation, resulting in late-embryonic lethality ofSin3B−/−mice.15In quiescent fibroblasts and hepatocytes, Sin3B is tethered to E2F target loci and represses transcription in a HDAC-dependent manner.15-17Consistent with these biochemical properties, Sin3B is required for quiescence upon serum starvation and for cellular senescence upon oncogene activation or serial passaging in mouse embryonic fibroblasts.15,18,19These experiments indicate that Sin3B modulates cell cycle withdrawal and differentiation in somatic cells. 2 SIN3B UNIPROT:O75182 activates GO:0030154 Phenotype b0268860-3387-11e8-87fd-001a4a160176 PMC5216265 However, terminal differentiation of specific lineages is impaired uponSin3Binactivation, resulting in late-embryonic lethality ofSin3B−/−mice.15In quiescent fibroblasts and hepatocytes, Sin3B is tethered to E2F target loci and represses transcription in a HDAC-dependent manner.15-17Consistent with these biochemical properties, Sin3B is required for quiescence upon serum starvation and for cellular senescence upon oncogene activation or serial passaging in mouse embryonic fibroblasts.15,18,19These experiments indicate that Sin3B modulates cell cycle withdrawal and differentiation in somatic cells. 2 SIN3B UNIPROT:O75182 activates GO:0090398 Phenotype 1bad42b0-c46b-11e5-8491-001a4ae51247 PMC4191901 Sin3b interacts with Hbp1 and recruits HDACs to silence proliferation-related genes and mediate cell cycle exit and senescence (David et al., 2008; Grandinetti et al., 2009; Swanson et al., 2004). 2 SIN3B UNIPROT:O75182 inhibits GO:0090398 Phenotype 80db8b9a-3513-11e8-87fd-001a4a160176 26564316 Surprisingly, SIN3B inactivation abrogated the senescence response, impaired inflammation, and delayed mPDAC progression. 2 SIN3B UNIPROT:O75182 activates GO:0006954 Phenotype 80db8b9a-3513-11e8-87fd-001a4a160176 26564316 Surprisingly, SIN3B inactivation abrogated the senescence response, impaired inflammation, and delayed mPDAC progression. 2 SIN3B UNIPROT:O75182 decreases MESH:D003094 Phenotype bc11bb42-c8e8-11e5-9624-001a4ae51246 17611194 Sin3B that assembles on the collagen gene to repress collagen gene transcription by transrepression. 2 SIN3B UNIPROT:O75182 inhibits GO:0016575 Phenotype cefe70fc-3749-11e8-87fd-001a4a160176 26130598 NuRD positively regulates elongation via its remodelling activity whereas the presence of Sin3B/HDAC1 is suggested to block elongation due to histone deacetylation. 2 SIN3B UNIPROT:O75182 activates GO:0044838 Phenotype b0268860-3387-11e8-87fd-001a4a160176 PMC5216265 Furthermore, we establish that Sin3B promotes HSC quiescence and protects animals from hematopoietic injury. 2 SIN3B UNIPROT:O75182 inhibits UNIPROT:Q9Y2W7 Protein fe35f960-34ed-11e9-913f-001a4a160175 PMC6324198 We confirmed the Sin3B deletion-induced de-repression of several E2F/DREAM targets using qRT-PCR in independent Sin3B-null cell lines (Figure 3C).|||Importantly, ectopic expression of Sin3B was sufficient to rescue the transcriptional repression of these DREAM targets in Sin3B-null quiescent cells (Figure 3D). 2 SIN3B UNIPROT:O75182 inhibits GO:0006351 Phenotype 1b5c49aa-c8da-11e5-9624-001a4ae51246 PMC4377314 We have previously demonstrated that Sin3B directly and specifically represses the transcription of several nuclear-encoded mitochondrial genes in differentiated myotubes (40).|||As we have recently demonstrated that Sin3B directly and specifically represses the transcription of several nuclear-encoded mitochondrial genes in differentiated myotubes (40), it is tempting to speculate that Sin3B levels and activities may alter mitochondrial metabolism, ultimately regulating ROS production. 2 SIN3B UNIPROT:O75182 activates GO:0090398 Phenotype ada5b8be-c470-11e5-8491-001a4ae51247 PMC2782780 Along with the normal p53 accumulation upon UV treatment in Sin3B−/−cells (Supplementary Fig. S3B), these results suggest that Sin3B acts downstream of the DNA damage response pathway to mediate senescence.|||Genetic inactivation of Sin3B prevents oncogene-induced senescence but is not sufficient for Ras-induced transformation.Given the requirement for Sin3B during replicative senescence (Fig. 1), we investigated whether a Sin3B-dependent pathway is equally engaged in oncogene-induced senescence. 2 SIN3B UNIPROT:O75182 activates GO:0090398 Phenotype fe35f960-34ed-11e9-913f-001a4a160175 PMC6324198 Finally, it is notable that Sin3B inactivation prevents oncogene-induced senescence, bothin vitroandin vivo.|||Interestingly,Sin3b-deleted cells are refractory to oncogene-induced senescence and, in some settings, exhibit altered terminal differentiation (Cantor and David, 2017; Dannenberg et al., 2005; David et al., 2008; Grandinetti et al., 2009; Rielland et al., 2014). 2 UNIPROT:P33076 activates SIN3B UNIPROT:O75182 Protein 65eeb082-c8e6-11e5-9ad8-001a4ae51247 17991736 Nonetheless, Sin3B consistently increased the repression by CIITA (data not shown). 2 UNIPROT:P48382 activates SIN3B UNIPROT:O75182 Protein e9981374-3531-11e8-87fd-001a4a160176 24709079 Intriguingly, deacetylation of RFX5 by HDAC2 promoted its interaction with Sin3B (Fig. 4L).|||On the other hand, silencing of RFX5 by shRNA blocked the binding of both RFX5 (Fig. 4C) and Sin3B (Fig. 4D), supporting an essential role for RFX5 in recruiting Sin3B to the collagen site. 2 UNIPROT:P01579 activates SIN3B UNIPROT:O75182 Protein e9981374-3531-11e8-87fd-001a4a160176 24709079 Furthermore, IFN-γ treatment increased the occupancy of G9a (Fig. 3B) and stimulated the formation of a Sin3B–G9a complex (Fig. 3C) on the collagen gene transcription start site as evidenced by ChIP and Re-ChIP assays, respectively.|||1B, Sin3B enhanced the repression ofCol1a2promoter activity by IFN-γ in a dose-dependent manner. 2 UNIPROT:Q5VTB9 deubiquitinatesProtein SIN3B UNIPROT:O75182 Protein 741dc870-bc00-11e5-8abe-001a4ae51246 10.1016/j.bbrc.2010.02.066 RNF220 promotes the ubiquitination and degradation of Sin3B According to the above results, we proposed that Sin3B may be a substrate for ubiquitination by RNF220.|||These results demonstrate that RNF220 can promote the ubiquitination and subsequent proteasomal degradation of Sin3B. 2 UNIPROT:Q5VTB9 ubiquitinatesProtein SIN3B UNIPROT:O75182 Protein 741dc870-bc00-11e5-8abe-001a4ae51246 10.1016/j.bbrc.2010.02.066 As expected, RNF220 could efficiently promote the polyubiquitination of Sin3B when co-transfected, while RNF220ΔRING couldn’t (Fig. 4D).|||The ubiquitination of Sin3B by RNF220 was investigated in transfected cells. 1 SIN3B UNIPROT:O75182 activates UNIPROT:P10599 Protein 04212b42-3834-11e6-b56c-001a4ae51246 PMC4905214 The SASP reinforces senescence in both an autocrine and a paracrine fashion, and recruits innate and adaptive immune cells.3Since PDAC relies on an inflammatory microenvironment, we postulated that the SASP, driven by Sin3B-dependent senescence, may paradoxically promote PDAC progression by recruiting immune cells that generate an inflammatory microenvironment. 1 SIN3B UNIPROT:O75182 activates UNIPROT:Q01538 Protein 0642f92c-ca03-11e5-ab20-001a4ae51246 PMC1201409 Following precipitation with an antibody directed against Sin3B, full-length Myt1 could be detected in cells transfected with Myt1 alone (Fig. 5a, lane 7), which was presumably mediated by endogenous Sin3B. 1 SIN3B UNIPROT:O75182 decreases UNIPROT:Q9Y2W7 Protein fe35f960-34ed-11e9-913f-001a4a160175 PMC6324198 RNA sequencing analysis revealed that Sin3B represses the expression of 140 DREAM target genes in quiescence. 1 SIN3B UNIPROT:O75182 inhibits UNIPROT:Q13547 Protein 9061843c-cc8a-11e5-888a-001a4ae51246 9197243 When Sin3B and Mad1 were coexpressed, the inhibitory effect of Mad1 was relieved partially, possibly because the overexpressed Sin3B sequesters endogenous HD1 or Rpd3-related enzymes. 1 SIN3B UNIPROT:O75182 inhibits UNIPROT:O15379 Protein 9061843c-cc8a-11e5-888a-001a4ae51246 9197243 When Sin3B and Mad1 were coexpressed, the inhibitory effect of Mad1 was relieved partially, possibly because the overexpressed Sin3B sequesters endogenous HD1 or Rpd3-related enzymes. 1 SIN3B UNIPROT:O75182 inhibits UNIPROT:Q13127 Protein a6261fac-5c27-11e7-8c5f-001a4ae51246 PMC5356016 Results Effect of knockdown of Sin3A or Sin3B on neuronal differentiation of P19 cells To examine whether suppression of Sin3A or Sin3B activity impedes the repressive function of REST and consequently enhances development of neuronal phenotypes, loss-of-function analyses were conducted in pluripotent P19 cells using Sin3A and Sin3B selective shRNAs. 1 SIN3B UNIPROT:O75182 activates UNIPROT:Q13127 Protein a6261fac-5c27-11e7-8c5f-001a4ae51246 PMC5356016 Results Effect of knockdown of Sin3A or Sin3B on neuronal differentiation of P19 cells To examine whether suppression of Sin3A or Sin3B activity impedes the repressive function of REST and consequently enhances development of neuronal phenotypes, loss-of-function analyses were conducted in pluripotent P19 cells using Sin3A and Sin3B selective shRNAs. 1 SIN3B UNIPROT:O75182 decreases UNIPROT:Q13127 Protein a6261fac-5c27-11e7-8c5f-001a4ae51246 PMC5356016 However, Sin3B knockdown caused a smaller effect on the expression of these REST target genes in P19 cells than Sin3A silencing. 1 SIN3B UNIPROT:O75182 deacetylatesProtein UNIPROT:P48382 Protein e9981374-3531-11e8-87fd-001a4a160176 24709079 Once deacetylated RFX5 then recruits Sin3B to the collagen site, which interacts with G9a and HDAC2 to remove histone H3 and H4 acetylation and augment H3K9 dimethylation establishing a repressive chromatin structure. 1 SIN3B UNIPROT:O75182 activates UNIPROT:P04637 Protein 9f4ceacc-bbf5-11e5-8abe-001a4ae51246 PMC4613689 We, now provide evidence that expression of Sin3B increases in p53-dependent manner under variety of stress conditions. 1 SIN3B UNIPROT:O75182 phosphorylatesProtein UNIPROT:P04637 Protein 9f4ceacc-bbf5-11e5-8abe-001a4ae51246 PMC4613689 Interestingly, in the present study, we observed that, association of Sin3B is increased with Ser15phosphorylated p53 under stress conditions. 1 SIN3B UNIPROT:O75182 inhibits UNIPROT:P12644 Protein 271b36d4-ab47-11e6-9ac8-001a4ae51246 PMC4914931 This evidence indicates a novel negative autoregulatory mechanism, where SIN3B can be alternatively spliced in response to BMP4, and then negatively regulate BMP4-dependent transcription. 1 SIN3B UNIPROT:O75182 activates UNIPROT:P08922 Protein 1b5c49aa-c8da-11e5-9624-001a4ae51246 PMC4377314 SinceSin3B−/−MEFs are resistant to premature senescence elicited by oncogene signaling and Bmi-1 depletion, we hypothesized that Sin3B levels may modulate ROS accumulation downstream of Bmi-1. 1 SIN3B UNIPROT:O75182 inhibits UNIPROT:P08922 Protein 1b5c49aa-c8da-11e5-9624-001a4ae51246 PMC4377314 How Sin3B prevents the accumulation of ROS is not entirely clear at this point. 1 SIN3B UNIPROT:O75182 decreases UNIPROT:P01106 Protein 3d5fe280-f58d-11eb-8cc9-001a4a160175 30012418 Published data suggests that Sin3b decreases Myc protein levels upon Myc deacetylation [54]. 1 SIN3B UNIPROT:O75182 activates UNIPROT:Q96ST3 Protein a6261fac-5c27-11e7-8c5f-001a4ae51246 PMC5356016 In addition, silencing of Sin3B enhances neuronal differentiation of P19 cells less efficiently than does Sin3A knockdown. 1 SIN3B UNIPROT:O75182 inhibits UNIPROT:Q96ST3 Protein 04157192-3906-11e8-a34b-001a4a160175 28057669 Whereas deletion of Sin3A caused early embryonic lethality, Sin3B deletion induced late embryonic lethality and impaired differentiation of, among others, erythroid and granulocytic progenitors.4,5Interestingly, conditional deletion of Sin3A in the bone marrow, using anMx-Cre;Sin3AΔ/Δmodel, quickly induced bone marrow failure as a consequence of a loss of stem and progenitor cells.6This phenotype was also observed upon simultaneous loss of HDAC1 and HDAC2, suggesting that Sin3A functions in HSCs within the context of the Sin3A/HDAC complex. 1 SIN3B UNIPROT:O75182 increases UNIPROT:Q96ST3 Protein a6261fac-5c27-11e7-8c5f-001a4ae51246 PMC5356016 The results showed that Sin3A and Sin3B knockdown in P19 cells mediated by shRNAs blocked the expression of the respective Sin3A and Sin3B genes without affecting the expression of the other genes, indicating that selective and efficient repression of each endogenous gene takes place (Supplementary Fig. S2). 1 SIN3B UNIPROT:O75182 increases UNIPROT:O75182 Protein ada5b8be-c470-11e5-8491-001a4ae51247 PMC2782780 Sin3B up-regulation is sufficient to induce senescence.We initially observed an increase in the level of Sin3B protein upon Ras induction (Fig. 2A). 1 SIN3B UNIPROT:O75182 increases UNIPROT:O75182 Protein a6261fac-5c27-11e7-8c5f-001a4ae51246 PMC5356016 The results showed that Sin3A and Sin3B knockdown in P19 cells mediated by shRNAs blocked the expression of the respective Sin3A and Sin3B genes without affecting the expression of the other genes, indicating that selective and efficient repression of each endogenous gene takes place (Supplementary Fig. S2). 1 SIN3B UNIPROT:O75182 increases UNIPROT:O75182 Protein 9f4ceacc-bbf5-11e5-8abe-001a4ae51246 PMC4613689 Negative regulation of subset of p53 target genes is Sin3B dependent To further validate the role of Sin3B in stress-induced p53-mediated gene repression of its target genes, we transfected the HCT116 cells with Sin3B shRNA to knockdown Sin3B (KDB) expression. 1 SIN3B UNIPROT:O75182 activates CHEBI:29101 Chemical f61ec200-bc11-11e5-8abe-001a4ae51246 PMC3786298 In agreement with this interpretation, Qmaxwas reduced by approximately 60% (P = 0.013) when Sin3B 293 was overexpressed (Fig. 7E), which is similar to the reduction in sodium current induced by Sin3B 293 (Fig. 6). 1 SIN3B UNIPROT:O75182 inhibits GO:0006351 Phenotype d087a920-bc1c-11e5-9b9d-001a4ae51247 PMC4222900 SIN3B (1, 5 dpa) represses transcription by serving as a scaffold to tether HDAC enzymes and thus prevent histone deacetylation. 1 SIN3B UNIPROT:O75182 activates GO:0022008 Phenotype a6261fac-5c27-11e7-8c5f-001a4ae51246 PMC5356016 Functionally active neurons are generated by knockdown of Sin3A in P19 cells As described above, Sin3A has a more profound effect on REST repressive machinery for silencing neuronal genes in P19 cells than Sin3B and suppression of Sin3A activity induces neurogenesis of the cells to a greater degree than that of Sin3B activity. 1 SIN3B UNIPROT:O75182 activates GO:0008283 Phenotype fe35f960-34ed-11e9-913f-001a4a160175 PMC6324198 These observations suggest that, under specific conditions, Sin3B inactivation allows quiescent cells to resume proliferation. 1 SIN3B UNIPROT:O75182 activates GO:0007049 Phenotype 541b53a0-5c16-11e7-9fde-001a4ae51247 PMC5448016 SIN3B interacts with HBP1 and recruits HDACs to silence proliferation-related genes and mediate cell cycle exit and senescence [115,116,117]. 1 SIN3B UNIPROT:O75182 activates GO:0007049 Phenotype f36ee256-34ea-11e9-8aa6-001a4a160176 PMC6295471 Moreover, loss of Sin3B in MEFs results in the absence of senescence upon oncogenic stress, while overexpression of Sin3B promotes cell cycle exit [93]. 1 SIN3B UNIPROT:O75182 activates GO:0048468 Phenotype 6c47f9be-bc54-11e5-ac4e-001a4ae51246 PMC2880436 Notably,Sin3b−/−embryos show defects in erythrocyte and granulocyte maturation similar to those seen in embryos deficient for known Sin3 interactors E2F4 and Mxd1 (Mad) (Foley et al., 1998; Humbert et al., 2000; Rempel et al., 2000), thereby providing evidence that Sin3b functions to promote E2F4- and Mxd1-dependent terminal differentiation of these lineages. 1 SIN3B UNIPROT:O75182 activates GO:0048468 Phenotype c889c44c-c8ec-11e5-878b-001a4ae51247 PMC2393767 Thus, Sin3B enables the terminal differentiation of multiple hematopoietic lineages. 1 SIN3B UNIPROT:O75182 inhibits GO:0007050 Phenotype cc9d8922-8dc3-11e7-82ff-001a4ae51246 PMC5311238 "Sin3B knockout mouse embryonic fibroblasts (MEFs) are refractory to quiescence and to oncogene-induced senescence (OIS), a stable cell cycle arrest in response to oncogene activation (10–13)." 1 SIN3B UNIPROT:O75182 activates GO:0030154 Phenotype 04157192-3906-11e8-a34b-001a4a160175 28057669 Whereas deletion of Sin3A caused early embryonic lethality, Sin3B deletion induced late embryonic lethality and impaired differentiation of, among others, erythroid and granulocytic progenitors.4,5Interestingly, conditional deletion of Sin3A in the bone marrow, using anMx-Cre;Sin3AΔ/Δmodel, quickly induced bone marrow failure as a consequence of a loss of stem and progenitor cells.6This phenotype was also observed upon simultaneous loss of HDAC1 and HDAC2, suggesting that Sin3A functions in HSCs within the context of the Sin3A/HDAC complex. 1 SIN3B UNIPROT:O75182 inhibits GO:0030154 Phenotype a6261fac-5c27-11e7-8c5f-001a4ae51246 PMC5356016 Rather, repression of Sin3A and Sin3B genes in pluripotent P19 cells induces neuronal differentiation with different levels of efficiency. 1 SIN3B UNIPROT:O75182 activates GO:0090398 Phenotype 1b5c49aa-c8da-11e5-9624-001a4ae51246 PMC4377314 Based on the demonstration that Sin3B is a direct target of Bmi-1 repression, and that Sin3B promotes replicative and oncogene-induced senescence (27), we investigated whether Sin3B upregulation contributed to the cellular senescence elicited upon a decrease in Bmi-1 levels. 1 SIN3B UNIPROT:O75182 inhibits GO:0090398 Phenotype cc9d8922-8dc3-11e7-82ff-001a4ae51246 PMC5311238 "Sin3B knockout mouse embryonic fibroblasts (MEFs) are refractory to quiescence and to oncogene-induced senescence (OIS), a stable cell cycle arrest in response to oncogene activation (10–13)." 1 SIN3B UNIPROT:O75182 inhibits GO:0090398 Phenotype fe35f960-34ed-11e9-913f-001a4a160175 PMC6324198 Finally, it is notable that Sin3B inactivation prevents oncogene-induced senescence, bothin vitroandin vivo. 1 SIN3B UNIPROT:O75182 inhibits GO:0090398 Phenotype ada5b8be-c470-11e5-8491-001a4ae51247 PMC2782780 Genetic inactivation of Sin3B prevents oncogene-induced senescence but is not sufficient for Ras-induced transformation.Given the requirement for Sin3B during replicative senescence (Fig. 1), we investigated whether a Sin3B-dependent pathway is equally engaged in oncogene-induced senescence. 1 SIN3B UNIPROT:O75182 inhibits MESH:D003094 Phenotype e9981374-3531-11e8-87fd-001a4a160176 24709079 Co-expression of G9a and Sin3B down-regulated the collagen promoter activity more potently than the expression of either protein individually did (Fig. 3D). 1 SIN3B UNIPROT:O75182 decreases MESH:D003094 Phenotype 9200d516-c471-11e5-8491-001a4ae51247 PMC2772741 "For example, GSK3/CKI phosphorylation of CIITA induces its interaction with the corepressor Sin3B, which accumulates on the collagen promoter and represses collagen transcription (34)." 1 SIN3B UNIPROT:O75182 increases MESH:D003094 Phenotype 9200d516-c471-11e5-8491-001a4ae51247 PMC2772741 "For example, GSK3/CKI phosphorylation of CIITA induces its interaction with the corepressor Sin3B, which accumulates on the collagen promoter and represses collagen transcription (34)." 1 SIN3B UNIPROT:O75182 inhibits GO:0016575 Phenotype d087a920-bc1c-11e5-9b9d-001a4ae51247 PMC4222900 SIN3B (1, 5 dpa) represses transcription by serving as a scaffold to tether HDAC enzymes and thus prevent histone deacetylation. 1 SIN3B UNIPROT:O75182 activates GO:0044838 Phenotype ada5b8be-c470-11e5-8491-001a4ae51247 PMC2782780 "Furthermore, genetic inactivation studies in the mouse showed that Sin3B, although dispensable for cellular growth, is necessary to mediate the onset of quiescence by transcriptional repression of E2F-responsive genes (19,20)." 1 SIN3B UNIPROT:O75182 inhibits GO:0090402 Phenotype cc9d8922-8dc3-11e7-82ff-001a4ae51246 PMC5311238 "Sin3B knockout mouse embryonic fibroblasts (MEFs) are refractory to quiescence and to oncogene-induced senescence (OIS), a stable cell cycle arrest in response to oncogene activation (10–13)." 1 SIN3B UNIPROT:O75182 decreases FPLX:Sodium:channels ProteinFamily f61ec200-bc11-11e5-8abe-001a4ae51246 PMC3786298 Sin3B 293 reduces sodium current and surface expression of sodium channels To determine if the interaction with Sin3B has any consequences for Nav-channel function, we overexpressed Sin3B 293 in the N1E-115 mouse neuroblastoma cell line and analyzed native sodium currents using the whole-cell patch-clamp technique 48 h after transfection. 1 SIN3B UNIPROT:O75182 inhibits FPLX:Histone ProteinFamily e9981374-3531-11e8-87fd-001a4a160176 24709079 Sin3B knockdown restored active histone marks including AcH3 (Fig. 2B), AcH4 (Fig. 2C), and H3K4Me3 (Fig. 2D) while prevented the accumulation of H3K9Me2 (Fig. 2E) on the collagen gene transcription start site in IFN-γ treated HASMCs. 1 SIN3B UNIPROT:O75182 decreases FPLX:COL1 ProteinFamily e9981374-3531-11e8-87fd-001a4a160176 24709079 Sin3B interacts with G9a to repress collagen type I transcription in smooth muscle cells Since we observed that Sin3B knockdown prevented the accumulation of H3K9Me2, catalyzed by the histone methyltransferase G9a[22], on the collagen gene transcription start site, we hypothesized that Sin3B might interact with G9a and engage G9a in collagen gene repression. 1 SIN3B UNIPROT:O75182 decreases FPLX:COL1 ProteinFamily 97548168-bbd7-11e5-9b9d-001a4ae51247 10.1016/j.ejcb.2013.09.001 On the one hand, transcription regulators like SMRT and MeCP2 have been shown to associate with mSin3A while on the other hand the master regulator of MHC II, CIITA, associates with HDAC2/Sin3B that mediate IFN-γ-induced repression of collagen type I gene transcription (Nagy et al., 1997; Nan et al., 1998; Xu et al., 2008). 1 SIN3B UNIPROT:O75182 inhibits FPLX:HDAC ProteinFamily f61ec200-bc11-11e5-8abe-001a4ae51246 PMC3786298 Therefore, is been proposed that Sin3B 293 could antagonize Sin3B/HDAC-mediated co-repression of genes24. 1 SIN3B UNIPROT:O75182 activates PF:PF06725 ProteinFamily ff2b94a0-ab16-11e6-807f-001a4ae51247 PMC5340233 SIN3B knockdown decreased invasiveness, promoted a more epithelial-like morphology in 3D, and decreased metastatic potential. 1 SIN3B UNIPROT:O75182 activates FPLX:RAS ProteinFamily ada5b8be-c470-11e5-8491-001a4ae51247 PMC2782780 Surprisingly, in Sin3B−/−cells overexpressing activated Ras, the level of p19ARFprotein was comparable with that detected in Sin3B+/+cells. 1 SIN3B UNIPROT:O75182 activates PF:PF00668 ProteinFamily 68f7a2a8-f58a-11eb-8bda-001a4a160175 30500349 Consequently, the SIN3B overexpression leads to the excessive chromatin condensation, which induces the formation of small- headed sperm in the patient. 1 SIN3B UNIPROT:O75182 decreases FPLX:MAP1LC3 ProteinFamily d9f424d2-c484-11e5-85e4-001a4ae51246 PMC3396506 "Just as the knockdown of SIN3A and SIN3B promotes an increase in cellular LC3 levels, inhibition of RPD3 promotes a similar increase (29⇓–31), although the detailed mechanism has not been determined." 1 UNIPROT:P15056 activates SIN3B UNIPROT:O75182 Protein 1b5c49aa-c8da-11e5-9624-001a4ae51246 PMC4377314 However, ectopic expression of oncogenic H-Ras or BRaf in immortalized MEFs that are unable to undergo senescence, also led to Sin3B upregulation (Figure 1E, 1F and 1G), suggesting that Sin3B levels are modulated by oncogenic signals rather than cellular senescence per se. 1 UNIPROT:Q01538 activates SIN3B UNIPROT:O75182 Protein 0642f92c-ca03-11e5-ab20-001a4ae51246 PMC1201409 Both MYT1 and Myt1L plasmids produced colonies with β-galactosidase activity in conjunction with Sin3B (Fig. 1c). 1 FPLX:Proteasome inhibits SIN3B UNIPROT:O75182 ProteinFamily 741dc870-bc00-11e5-8abe-001a4ae51246 10.1016/j.bbrc.2010.02.066 We then examined whether RNF220 could stimulate the proteasome-dependent degradation of Sin3B. 1 UNIPROT:Q9UKT4 activates SIN3B UNIPROT:O75182 Protein fe35f960-34ed-11e9-913f-001a4a160175 PMC6324198 Strikingly, ectopic expression of the APC/CCDH1inhibitor EMI1 was sufficient to promote cell-cycle re-entry of Sin3B deleted cells under serum-deprived conditions, while the Sin3B wild-type cells remained quiescent. 1 UNIPROT:P61244 inhibits SIN3B UNIPROT:O75182 Protein 22021312-c479-11e5-8491-001a4ae51247 PMC3196102 Max/Mnt dimers repress transcription by recruiting the Sin3a or Sin3b co-repressors (31), so we also investigated binding of Sin3a and Sin3b. 1 UNIPROT:Q13127 activates SIN3B UNIPROT:O75182 Protein ad7a2510-8dbd-11e7-b4f4-001a4ae51246 PMC5255626 Several studies have shown that REST can mediate repression independent of RCOR proteins by recruiting the corepressors SIN3A, SIN3B, or CDYL (46⇓⇓–49). 1 FPLX:CREB inhibits SIN3B UNIPROT:O75182 ProteinFamily 0ae8110c-a073-11ee-ae1b-0050569a1f61 10.1007/s12640-020-00317-7 Convington et al. (6) also showed that MS-275 decreased HDAC2 expression in the nucleus accumbens and simultaneously increased H3 acetylation, level of CREB, co-REST, and up-regulated some genes (slc17a,nrn1,rab3b,TNFRSF1A,sin3b). 1 UNIPROT:P01112 activates SIN3B UNIPROT:O75182 Protein 1b5c49aa-c8da-11e5-9624-001a4ae51246 PMC4377314 However, ectopic expression of oncogenic H-Ras or BRaf in immortalized MEFs that are unable to undergo senescence, also led to Sin3B upregulation (Figure 1E, 1F and 1G), suggesting that Sin3B levels are modulated by oncogenic signals rather than cellular senescence per se. 1 UNIPROT:O43663 decreases SIN3B UNIPROT:O75182 Protein 1b5c49aa-c8da-11e5-9624-001a4ae51246 PMC4377314 The PRC1 component Bmi-1 represses Sin3B expression in proliferating cells The results presented above indicate that the Sin3B locus is maintained in a relative transcriptionally repressed state in proliferating cells but becomes activated upon oncogene activation. 1 UNIPROT:P55273 increases SIN3B UNIPROT:O75182 Protein a6261fac-5c27-11e7-8c5f-001a4ae51246 PMC5356016 The results showed that Sin3A and Sin3B knockdown in P19 cells mediated by shRNAs blocked the expression of the respective Sin3A and Sin3B genes without affecting the expression of the other genes, indicating that selective and efficient repression of each endogenous gene takes place (Supplementary Fig. S2). 1 UNIPROT:P55273 inhibits SIN3B UNIPROT:O75182 Protein a6261fac-5c27-11e7-8c5f-001a4ae51246 PMC5356016 Neurogenesis of Sin3A and Sin3B knockdown P19 cells Sin3A- and Sin3B-knockdown P19 cells were seeded at a density of 106cells/mL in 90 mm petri dishes under non-adherent culture conditions and allowed to aggregate for 3 days. 1 UNIPROT:Q9UL68 activates SIN3B UNIPROT:O75182 Protein 0642f92c-ca03-11e5-ab20-001a4ae51246 PMC1201409 Both MYT1 and Myt1L plasmids produced colonies with β-galactosidase activity in conjunction with Sin3B (Fig. 1c). 1 FPLX:BMP activates SIN3B UNIPROT:O75182 ProteinFamily 271b36d4-ab47-11e6-9ac8-001a4ae51246 PMC4914931 Profiling such a network will require significant effort, but would be necessary to appreciate the intermediate steps between BMP pathway activation and RBM39 mediated splicing of SIN3B. 1 FPLX:RAS increases SIN3B UNIPROT:O75182 ProteinFamily ada5b8be-c470-11e5-8491-001a4ae51247 PMC2782780 "As shown by quantitative reverse transcription-PCR (RT-PCR) analysis, the increase in Sin3B levels upon activated Ras expression occurs at the transcriptional level (Fig. 4A, right)." 1 FPLX:RAS activates SIN3B UNIPROT:O75182 ProteinFamily 97548168-bbd7-11e5-9b9d-001a4ae51247 10.1016/j.ejcb.2013.09.001 A subsequent paper by the same group demonstrated that Sin3B is upregulated during oncogenic stress, signaled by Ras overexpression and is required for cellular senescence (Grandinetti et al., 2009). 1 UNIPROT:P04637 phosphorylatesProtein SIN3B UNIPROT:O75182 Protein a0b4bdb8-bc36-11e5-8d2d-001a4ae51247 PMC3197607 Results Human p53 co-immunoprecipitates phosphorylated human Sin3B To investigate the role of human Sin3B (hSin3B) in p53 trans-repression functions, we initially performed co-immunoprecipitation assays to test the association between p53 and hSin3B in three different human cell lines. 1 UNIPROT:Q99583 inhibits SIN3B UNIPROT:O75182 Protein 22021312-c479-11e5-8491-001a4ae51247 PMC3196102 Max/Mnt dimers repress transcription by recruiting the Sin3a or Sin3b co-repressors (31), so we also investigated binding of Sin3a and Sin3b. 1 UNIPROT:O48686 inhibits SIN3B UNIPROT:O75182 Protein ff2b94a0-ab16-11e6-807f-001a4ae51247 PMC5340233 This is consistent with recent studies demonstrating inhibition of breast cancer invasion using SIN3 interacting domain decoy peptides and small molecule inhibitors of SIN3 that inhibit both SIN3A and SIN3B [16,17]. 1 UNIPROT:Q92769 inhibits SIN3B UNIPROT:O75182 Protein 0ae8110c-a073-11ee-ae1b-0050569a1f61 10.1007/s12640-020-00317-7 Convington et al. (6) also showed that MS-275 decreased HDAC2 expression in the nucleus accumbens and simultaneously increased H3 acetylation, level of CREB, co-REST, and up-regulated some genes (slc17a,nrn1,rab3b,TNFRSF1A,sin3b). 1 UNIPROT:Q9UKL0 inhibits SIN3B UNIPROT:O75182 Protein 0ae8110c-a073-11ee-ae1b-0050569a1f61 10.1007/s12640-020-00317-7 Convington et al. (6) also showed that MS-275 decreased HDAC2 expression in the nucleus accumbens and simultaneously increased H3 acetylation, level of CREB, co-REST, and up-regulated some genes (slc17a,nrn1,rab3b,TNFRSF1A,sin3b). 1 FPLX:Histone:H3 inhibits SIN3B UNIPROT:O75182 ProteinFamily 0ae8110c-a073-11ee-ae1b-0050569a1f61 10.1007/s12640-020-00317-7 Convington et al. (6) also showed that MS-275 decreased HDAC2 expression in the nucleus accumbens and simultaneously increased H3 acetylation, level of CREB, co-REST, and up-regulated some genes (slc17a,nrn1,rab3b,TNFRSF1A,sin3b). 1 UNIPROT:P35226 increases SIN3B UNIPROT:O75182 Protein 1b5c49aa-c8da-11e5-9624-001a4ae51246 PMC4377314 To examine the molecular mechanisms underlying Bmi-1 modulation of Sin3B expression, we performed Chromatin ImmunoPrecipitation (ChIP) experiments on primary MEFs, before or after BRafV600Eactivation. 1 UNIPROT:P35226 inhibits SIN3B UNIPROT:O75182 Protein 1b5c49aa-c8da-11e5-9624-001a4ae51246 PMC4377314 Importantly, Bmi-1 driven repression of Sin3B is specific, as the protein levels of the closely related Sin3A were not affected by Bmi-1 ectopic expression (Supplementary Figure 1A). 1 UNIPROT:Q5VTB9 inhibits SIN3B UNIPROT:O75182 Protein 741dc870-bc00-11e5-8abe-001a4ae51246 10.1016/j.bbrc.2010.02.066 We then examined whether RNF220 could stimulate the proteasome-dependent degradation of Sin3B. 1 UNIPROT:Q5VTB9 ubiquitinatesProtein SIN3B UNIPROT:O75182 Protein 33f276d4-c46f-11e5-9cc6-001a4ae51246 PMC4248747 "Indeed, RNF220 (W539R) failed to promote the ubiquitination of Sin3B (data not shown), an established target protein of RNF220 (22)." 1 UNIPROT:Q96ST3 activates SIN3B UNIPROT:O75182 Protein 5010f46a-c480-11e5-8491-001a4ae51247 PMC3004272 "Collectively, our data (i) strongly suggest that a subset of sarcomeric genes are directly activated by Sin3A and Sin3B and (ii) provide a molecular explanation for the enhanced phenotype observed upon inactivation of both Sin3A and Sin3B, compared to what was found for inactivation of Sin3A alone, and the lack of overt alterations associated with inactivation of Sin3Bin vivoandin vitro(Fig.2and3)." 1 UNIPROT:Q96ST3 increases SIN3B UNIPROT:O75182 Protein a6261fac-5c27-11e7-8c5f-001a4ae51246 PMC5356016 The results showed that Sin3A and Sin3B knockdown in P19 cells mediated by shRNAs blocked the expression of the respective Sin3A and Sin3B genes without affecting the expression of the other genes, indicating that selective and efficient repression of each endogenous gene takes place (Supplementary Fig. S2). 1 CHEBI:75142 inhibits SIN3B UNIPROT:O75182 Chemical 741dc870-bc00-11e5-8abe-001a4ae51246 10.1016/j.bbrc.2010.02.066 Addition of the proteasome inhibitor MG132 enhanced the staining of Sin3B (Fig. 3B, middle panel). 1 UNIPROT:O75182 increases SIN3B UNIPROT:O75182 Protein 9f4ceacc-bbf5-11e5-8abe-001a4ae51246 PMC4613689 Negative regulation of subset of p53 target genes is Sin3B dependent To further validate the role of Sin3B in stress-induced p53-mediated gene repression of its target genes, we transfected the HCT116 cells with Sin3B shRNA to knockdown Sin3B (KDB) expression. 1 UNIPROT:O75182 increases SIN3B UNIPROT:O75182 Protein ada5b8be-c470-11e5-8491-001a4ae51247 PMC2782780 Sin3B up-regulation is sufficient to induce senescence.We initially observed an increase in the level of Sin3B protein upon Ras induction (Fig. 2A). 1 UNIPROT:O75182 increases SIN3B UNIPROT:O75182 Protein a6261fac-5c27-11e7-8c5f-001a4ae51246 PMC5356016 The results showed that Sin3A and Sin3B knockdown in P19 cells mediated by shRNAs blocked the expression of the respective Sin3A and Sin3B genes without affecting the expression of the other genes, indicating that selective and efficient repression of each endogenous gene takes place (Supplementary Fig. S2).