Sumoylation activates the transcriptional activity of Pax-6, an important transcription factor for eye and brain development

Yan, Qin; Gong, Lili; Deng, Mi; Zhang, Lan; Sun, Shuming; Liu, Jiao; Ma, Haili; Yuan, Dan; Chen, Pei Chao; Hu, Xiaohui; Liu, Jinping; Qin, Jianbing; Xiao, Ling; Huang, Xingxing; Zhang, Jian; Li, David Wan Cheng

doi:10.1073/pnas.1007866107

Cited by 81 publications

(83 citation statements)

References 32 publications

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“…In contrast, during calcium-induced keratinocyte differentiation, overall enhanced SUMO1 modifications were accompanied by up-regulation of sumoylation system components (9). Although it is now well-established that sumoylation plays important roles in regulating cell differentiation (8)(9)(10)(11)(12), little is known regarding the impact of the individual SUMO paralogues. An early study has shown that haploinsufficiency of SUMO1 led to cleft lip and palate in embryonic mice (5), suggesting that SUMO2/3 do not substitute for SUMO1.…”

Section: Discussionmentioning

confidence: 93%

“…In ocular tissues, sumoylation helps to determine the differentiation of cone versus rod photoreceptors (11). Our recent study revealed that SUMO1-mediated sumoylation is an indispensable step toward activation of p32 Pax-6, a master regulator of eye and brain development (12). Although the effects of sumoylation on individual targets in regulating cell differentiation and other biological processes are being unraveled, it remains largely unknown how SUMO isoforms regulate cell differentiation and whether SUMO1 and SUMO2/3 display distinct functions.…”

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confidence: 99%

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Sumoylation differentially regulates Sp1 to control cell differentiation

Gong

et al. 2014

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

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The mammalian small ubiquitin-like modifiers (SUMOs) are actively involved in regulating differentiation of different cell types. However, the functional differences between SUMO isoforms and their mechanisms of action remain largely unknown. Using the ocular lens as a model system, we demonstrate that different SUMOs display distinct functions in regulating differentiation of epithelial cells into fiber cells. During lens differentiation, SUMO1 and SUMO2/3 displayed different expression, localization, and targets, suggesting differential functions. Indeed, overexpression of SUMO2/3, but not SUMO1, inhibited basic (b) FGF-induced cell differentiation. In contrast, knockdown of SUMO1, but not SUMO2/3, also inhibited bFGF action. Mechanistically, specificity protein 1 (Sp1), a major transcription factor that controls expression of lens-specific genes such as β-crystallins, was positively regulated by SUMO1 but negatively regulated by SUMO2. SUMO2 was found to inhibit Sp1 functions through several mechanisms: sumoylating it at K683 to attenuate DNA binding, and at K16 to increase its turnover. SUMO2 also interfered with the interaction between Sp1 and the coactivator, p300, and recruited a repressor, Sp3 to β-crystallin gene promoters, to negatively regulate their expression. Thus, stable SUMO1, but diminishing SUMO2/3, during lens development is necessary for normal lens differentiation. In support of this conclusion, SUMO1 and Sp1 formed complexes during early and later stages of lens development. In contrast, an interaction between SUMO2/3 and Sp1 was detected only during the initial lens vesicle stage. Together, our results establish distinct roles of different SUMO isoforms and demonstrate for the first time, to our knowledge, that Sp1 acts as a major transcription factor target for SUMO control of cell differentiation.transcription regulation | eye development | crystallin gene expression T he conjugation of small ubiquitin-like modifiers (SUMOs) to protein substrates (named sumoylation) is a critical posttranslational modification with diverse cellular functions (1). Three major SUMO isoforms (SUMO1, -2, and -3) were identified in vertebrates. Although the mature SUMO2 and SUMO3 share a very high level of sequence identity (97%) and cannot be immunologically discriminated (thus referred to as SUMO2/3), they significantly differ from SUMO1, with only 45% identity (2, 3). Recent studies using proteomics revealed that SUMO1 and SUMO2/3 can be targeted to both distinct and overlapping sets of substrates (4). However, whether SUMO1 and SUMO2/3 have redundant or different functions in vivo is not clear because inconsistent results have been reported in SUMO1 knockout mice (5, 6). SUMO conjugation is executed by three enzymes. The activating enzyme E1, a heterodimer of SAE1 and SAE2, transfers SUMO to the single E2-conjugating enzyme Ubc9, which either sumoylates the substrate alone, or cofunctions with different E3 ligases. Sumoylation is highly dynamic and can be rapidly reverted by sentrin-specific proteases (SE...

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Section: Discussionmentioning

confidence: 93%

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confidence: 99%

Sumoylation differentially regulates Sp1 to control cell differentiation

Gong

et al. 2014

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

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“…This phosphorylation enhances the transcriptional activities of PAX family proteins. In addition, PAX6 phosphorylation by homeodomain-interacting protein kinase 2 (31), sumoylation of PAX6 (32), and acetylation of PAX5 by p300 (33) are reported to be posttranslational modifications of PAX family proteins, and all enhance the transactivation of PAX family proteins; therefore, negative regulation of PAX5 function by phosphorylation seems to be unique. Serines of PAX5 phosphorylation sites are not conserved in any other PAX family proteins.…”

Section: Discussionmentioning

confidence: 99%

B Cell Receptor-ERK1/2 Signal Cancels PAX5-Dependent Repression of BLIMP1 through PAX5 Phosphorylation: A Mechanism of Antigen-Triggering Plasma Cell Differentiation

Yasuda

Hayakawa

Kurahashi

et al. 2012

The Journal of Immunology

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Plasma cell differentiation is initiated by Ag stimulation of BCR. Until BCR stimulation, B lymphocyte-induced maturation protein 1 (BLIMP1), a master regulator of plasma cell differentiation, is suppressed by PAX5, which is a key transcriptional repressor for maintaining B cell identity. After BCR stimulation, upregulation of BLIMP1 and subsequent suppression of PAX5 by BLIMP1 are observed and thought to be the trigger of plasma cell differentiation; however, the trigger that derepresses BLIMP1 expression is yet to be revealed. In this study, we demonstrated PAX5 phosphorylation by ERK1/2, the main component of the BCR signal. Transcriptional repression on BLIMP1 promoter by PAX5 was canceled by PAX5 phosphorylation. BCR stimulation induced ERK1/2 activation, phosphorylation of endogenous PAX5, and upregulation of BLIMP1 mRNA expression in B cells. These phenomena were inhibited by MEK1 inhibitor or the phosphorylation-defective mutation of PAX5. These data imply that PAX5 phosphorylation by the BCR signal is the initial event in plasma cell differentiation.

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“…A number of transcription factors are regulated by SUMO modification. SUMOdependent transcriptional stimulation has been reported for GATA4, PAX6, and the glucocorticoid receptor (13)(14)(15). However, SUMO modification more frequently results in transcriptional repression, as is the case for c-Jun, C/EBP family members, Sp3, IB␣, KAP-1, PPAR␥, and a number of other transcription factors (16 -19).…”

Section: Dna Replication-related Element Binding Factor (Dref)mentioning

confidence: 99%

Transcription Factor hDREF Is a Novel SUMO E3 Ligase of Mi2α

Yamashita

Moriuchi

Osumi

et al. 2016

Journal of Biological Chemistry

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The human transcription factor DNA replication-related element-binding factor (hDREF) is essential for the transcription of a number of housekeeping genes. The mechanisms underlying constitutively active transcription by hDREF were unclear. Here, we provide evidence that hDREF possesses small ubiquitin-like modifier (SUMO) ligase activity and can specifically SUMOylate Mi2␣, an ATP-dependent DNA helicase in the nucleosome remodeling and deacetylation complex. Moreover, immunofluorescent staining and biochemical analyses showed that coexpression of hDREF and SUMO-1 resulted in dissociation of Mi2␣ from chromatin, whereas a SUMOylation-defective Mi2␣ mutant remained tightly bound to chromatin. Chromatin immunoprecipitation and quantitative RT-PCR analysis demonstrated that Mi2␣ expression diminished transcription of the ribosomal protein genes, which are positively regulated by hDREF. In contrast, coexpression of hDREF and SUMO-1 suppressed the transcriptional repression by Mi2␣. These data indicate that hDREF might incite transcriptional activation by SUMOylating Mi2␣, resulting in the dissociation of Mi2␣ from the gene loci. We propose a novel mechanism for maintaining constitutively active states of a number of hDREF target genes through SUMOylation.

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Sumoylation activates the transcriptional activity of Pax-6, an important transcription factor for eye and brain development

Cited by 81 publications

References 32 publications

Sumoylation differentially regulates Sp1 to control cell differentiation

Sumoylation differentially regulates Sp1 to control cell differentiation

B Cell Receptor-ERK1/2 Signal Cancels PAX5-Dependent Repression of BLIMP1 through PAX5 Phosphorylation: A Mechanism of Antigen-Triggering Plasma Cell Differentiation

Transcription Factor hDREF Is a Novel SUMO E3 Ligase of Mi2α

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