Phosphorylation-Dependent Control of Pc2 SUMO E3 Ligase Activity by Its Substrate Protein HIPK2

Roscic, Ana; Möller, Andreas; Calzado, Marco A.; Renner, Florian; Wimmer, Verena C.; Gresko, Ekaterina; Lüdi, Katharina Schmid; Schmitz, M. Lienhard

doi:10.1016/j.molcel.2006.08.004

Cited by 120 publications

(102 citation statements)

References 50 publications

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“…Nuclear translocation of the CLOCK/BMAL1 heterodimer is essential to activate E-box-dependent clock gene transcription (30,42). Sumoylation often affects the subcellular localization of target proteins (32,37). To investigate the relationship between the subcellular localization of BMAL1 and its sumoylation, we first examined the distribution of BMAL1 tagged with green fluorescent protein at its N terminus (GFP-BMAL1) and endogenous SUMO paralogues in COS-7 cells.…”

Section: Resultsmentioning

confidence: 99%

Dual Modification of BMAL1 by SUMO2/3 and Ubiquitin Promotes Circadian Activation of the CLOCK/BMAL1 Complex

Lee

et al. 2008

Molecular and Cellular Biology

142

145

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Heterodimers of BMAL1 and CLOCK drive rhythmic expression of clock-controlled genes, thereby generating circadian physiology and behavior. Posttranslational modifications of BMAL1 play a key role in modulating the transcriptional activity of the CLOCK/BMAL1 complex during the circadian cycle. Recently, we demonstrated that circadian activation of the heterodimeric transcription factor is accompanied by ubiquitindependent proteolysis of BMAL1. Here we show that modification by SUMO localizes BMAL1 exclusively to the promyelocytic leukemia nuclear body (NB) and simultaneously promotes its transactivation and ubiquitindependent degradation. Under physiological conditions, BMAL1 was predominantly conjugated to poly-SUMO2/3 rather than SUMO1, and the level of these conjugates underwent rhythmic variation, peaking at times of maximum E-box-mediated circadian transcription. Interestingly, mutation of the sumoylation site (Lys 259 ) of BMAL1 markedly inhibited both its ubiquitination and its proteasome-mediated proteolysis, and these effects were reversed by covalent attachment of SUMO3 to the C terminus of the mutant BMAL1. Consistent with this, SUSP1, a SUMO protease highly specific for SUMO2/3, abolished ubiquitination, as well as sumoylation of BMAL1, while the ubiquitin protease UBP41 blocked BMAL1 ubiquitination but induced accumulation of polysumoylated BMAL1 and its localization to the NB. Furthermore, inhibition of proteasome with MG132 elicited robust nuclear accumulation of SUMO2/3-and ubiquitin-modified BMAL1 that was restricted to the transcriptionally active stage of the circadian cycle. These results indicate that dual modification of BMAL1 by SUMO2/3 and ubiquitin is essential for circadian activation and degradation of the CLOCK/BMAL1 complex.Circadian rhythms are fundamental mechanisms that optimize the physiology and behavior of most organisms. Extensive genetic and molecular studies have shown that these biological rhythms are driven by molecular clockwork composed of autoregulatory transcription-translation feedback loops involving several clock gene products (27,36). In mammals, the heterodimeric transcription factor CLOCK/ BMAL1 activates transcription of its own negative regulators, including cryptochromes (CRYs) and periods (PERs), and the products of the newly synthesized transcripts form complexes that block their own transcription by binding to the heterodimeric transcription activator. Of the negative regulators, the CRYs play a central role in this feedback inhibition by interacting directly with the C terminus of BMAL1 (15,26,29).There is, however, some evidence that this canonical feedback mechanism is insufficient to account for the robust oscillation of the circadian clock. During the circadian cycle, the mRNA profiles of the key negative regulators, the CRYs, exhibit weak oscillations compared to those of other clock genes controlled by the CLOCK/BMAL1 complex (14,31,35). Moreover, the abundance of BMAL1 and CLOCK proteins in the nucleus reaches a minimum at the time that expression of...

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Section: Resultsmentioning

confidence: 99%

Dual Modification of BMAL1 by SUMO2/3 and Ubiquitin Promotes Circadian Activation of the CLOCK/BMAL1 Complex

Lee

et al. 2008

Molecular and Cellular Biology

142

145

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“…The classification of members of the Cbx family is based on the presence of a single N-terminal chromodomain ( Figure 1A), which, in at least some members of the family, can bind to histone proteins via methylated lysine residues [51]. More interestingly, human Cbx4 (also known as polycomb 2, Pc2) also has SUMO E3 ligase activity [51], for which a limited repertoire of substrates have been identified, including C-terminus binding protein 1 [52], DNA methyltransferase 3a [53], Smad-interacting Protein 1 [54], centrin-2 [55], and homeodomain-interacting protein kinase 2 [56].…”

Section: Cbx4 and Hif-1 Sumoylationmentioning

confidence: 99%

Sumoylation of hypoxia inducible factor-1α and its significance in cancer

Jiao

et al. 2014

Sci. China Life Sci.

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Hypoxia-inducible factor-1 (HIF-1) is a key heterodimeric transcription factor for the cellular adaptive response to hypoxia, a common feature of the microenvironment in solid tumors. The transcriptional activity, protein stabilization, protein-protein interactions and cellular localization of HIF-1, an oxygen-sensitive subunit of HIF-1, are mainly modulated by various post-translational modifications. Recently, we reported that polycomb chromobox 4 (Cbx4) governs the transcriptional activity of HIF-1α by enhancing its sumoylation at K391 and K477, through which Cbx4 potentiates angiogenesis of hepatocellular carcinoma. This review summarizes the current knowledge of HIF-1 sumoylation and its roles in the pathogenesis of cancer.

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“…Thus, sumoylation contributes to the regulation of ABA signaling. In animal cells, the SUMO E3 ligase Pc2 is phosphorylated by the protein kinase HIPK2 (Roscic et al, 2006). Regulation of the ABA signaling pathway in which sumoylation is implicated is possibly achieved by Tyr phosphorylation.…”

Section: Tyr Phosphorylation Of Putative Aba Signaling Elements In Armentioning

confidence: 99%

Protein Tyrosine Kinases and Protein Tyrosine Phosphatases Are Involved in Abscisic Acid-Dependent Processes in Arabidopsis Seeds and Suspension Cells

et al. 2008

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Protein tyrosine (Tyr) phosphorylation plays a central role in many signaling pathways leading to cell growth and differentiation in animals. Tyr phosphorylated proteins have been detected in higher plants, and the roles of protein Tyr phosphatases and protein Tyr kinases in some physiological responses have been shown. We investigated the involvement of Tyr phosphorylation events in abscisic acid (ABA) signaling using a pharmacological approach. Phenylarsine oxide, a specific inhibitor of protein Tyr phosphatase activity, abolished the ABA-dependent accumulation of RAB18 (responsive to ABA 18) transcripts. Protein Tyr kinase inhibitors like genistein, tyrphostin A23, and erbstatin blocked the RAB18 expression induced by ABA in Arabidopsis (Arabidopsis thaliana). Stomatal closure induced by ABA was also inhibited by phenylarsine oxide and genistein. We studied the changes in the Tyr phosphorylation levels of proteins in Arabidopsis seeds after ABA treatment. Proteins were separated by two-dimensional gel electrophoresis, and those phosphorylated on Tyr residues were detected using an anti-phosphotyrosine antibody by western blot. Changes were detected in the Tyr phosphorylation levels of 19 proteins after ABA treatment. Genistein inhibited the ABA-dependent Tyr phosphorylation of proteins. The 19 proteins were analyzed by matrix-assisted laser-desorption ionization time-of-flight/time-of-flight mass spectrometry. Among the proteins identified were storage proteins like cruciferins, enzymes involved in the mobilization of lipid reserves like aconitase, enolase, aldolase, and a lipoprotein, and enzymes necessary for seedling development like the large subunit of Rubisco. Additionally, the identification of three putative signaling proteins, a peptidyl-prolyl isomerase, an RNA-binding protein, and a small ubiquitin-like modifier-conjugating enzyme, enlightens how Tyr phosphorylation might regulate ABA transduction pathways in plants.

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Phosphorylation-Dependent Control of Pc2 SUMO E3 Ligase Activity by Its Substrate Protein HIPK2

Cited by 120 publications

References 50 publications

Dual Modification of BMAL1 by SUMO2/3 and Ubiquitin Promotes Circadian Activation of the CLOCK/BMAL1 Complex

Dual Modification of BMAL1 by SUMO2/3 and Ubiquitin Promotes Circadian Activation of the CLOCK/BMAL1 Complex

Sumoylation of hypoxia inducible factor-1α and its significance in cancer

Protein Tyrosine Kinases and Protein Tyrosine Phosphatases Are Involved in Abscisic Acid-Dependent Processes in Arabidopsis Seeds and Suspension Cells

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