Homeodomain-interacting Protein Kinases, a Novel Family of Co-repressors for Homeodomain Transcription Factors

Kim, Young Ho; Choi, Cheol Yong; Lee, Seung-Jae; Conti, Mary Anne; Kim, Yongsok

doi:10.1074/jbc.273.40.25875

Cited by 265 publications

(274 citation statements)

References 25 publications

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“…The expression plasmids for GFP-and Myc-tagged SENP1 and HIPK1 were generated by inserting human SENP1 or mouse HIPK1 cDNA into pEGFP-C2 and pCS3 þ MTBX, respectively, as described previously for HIPK2. 13,15 The mutant SENP1 (C602A) was constructed by site-directed mutagenesis using Quickchanget site-directed mutagenesis kit (Stratagene) according to the protocol of the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

“…13,14 The HIPKs were originally identified as nuclear protein kinases that function as co-repressors for various homeodomain-containing transcription factors. 15 Recently, HIPKs have been shown to interact with other proteins involved in apoptosis and signal transduction in a cellular localization-dependent manner. In nucleus, HIPK2 phosphorylates p53 on Ser 46, resulting in the activation of p53-dependent transcription, cell growth regulation, and apoptosis initiation.…”

mentioning

confidence: 99%

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SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis

Luo

et al. 2008

Cell Death Differ

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We have previously shown that tumor necrosis factor (TNF)-induced desumoylation and subsequent cytoplasmic translocation of HIPK1 are critical for ASK1-JNK activation. However, the mechanism by which TNF induces desumoylation of HIPK1 is unclear. Here, we show that SENP1, a SUMO-specific protease, specifically deconjugates SUMO from HIPK1 in vitro and in vivo. In resting endothelial cells (ECs), SENP1 is localized in the cytoplasm where it is complexed with an antioxidant protein thioredoxin. TNF induces the release of SENP1 from thioredoxin as well as nuclear translocation of SENP1. TNF-induced SENP1 nuclear translocation is specifically blocked by antioxidants such as N-acetyl-cysteine, suggesting that TNF-induced translocation of SENP1 is ROS dependent. TNF-induced nuclear import of SENP1 kinetically correlates with HIPK1 desumoylation and cytoplasmic translocation. Furthermore, the wild-type form of SENP1 enhances, whereas the catalyticinactive mutant form or siRNA of SENP1 blocks, TNF-induced desumoylation and cytoplasmic translocation of HIPK1 as well as TNF-induced ASK1-JNK activation. More importantly, these critical functions of SENP1 in TNF signaling were further confirmed in mouse embryonic fibroblast cells derived from SENP1-knockout mice. We conclude that SENP1 mediates TNF-induced desumoylation and translocation of HIPK1, leading to an enhanced ASK1-dependent apoptosis. The small ubiquitin-like modifier (SUMO) can be covalently attached to a large number of proteins through the formation of isopeptide bonds with specific lysine residues of target proteins. 1,2 A large number of sumoylated proteins, including RanGAP1, PML, homeodomain-interacting protein kinases (HIPKs), IkB, p53, c-Jun, Sp3, Elk-1, p300 histone acetyltransferase, histone deacetylase (HDAC), and many nuclear receptors, have been identified. 1-3 Sumoylation is a dynamic process that is mediated by activating, conjugating, and ligating enzymes and that is readily reversed by a family of SUMO-specific proteases. 4 Several members of SUMOspecific proteases have been reported in the mammalian system. 5-10 SENP1 is a protease that appears to deconjugate a large number of sumoylated proteins. 5 Different members of these SUMO-specific proteases appear to localize in different cellular compartments where they regulate protein function by modifying the protein stability, cellular localization, and protein-protein interactions. 5,6,[8][9][10][11][12] However, it is not known how these SUMO-specific proteases are regulated.HIPK1 is one of three closely related serine/threonine protein kinases that are primarily localized in the nucleus where it is sumoylated. 13,14 The HIPKs were originally identified as nuclear protein kinases that function as co-repressors for various homeodomain-containing transcription factors. 15 Recently, HIPKs have been shown to interact with other proteins involved in apoptosis and signal transduction in a cellular localization-dependent manner. In nucleus, HIPK2 phosphorylates p53 on Ser 46, resulting in the activatio...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis

Luo

et al. 2008

Cell Death Differ

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“…In humans and mice the family comprises three Function of PML in apoptosis regulation TG Hofmann and H Will members, HIPK1-3, which were originally identified as corepressors for homeodomain transcription factors. 89 HIPKs belong to the dual-specificity tyrosine phosphorylation-regulated kinase family of protein kinases 90 and function in transcriptional regulation, 91,92 growth suppression 93 and apoptosis. 24,25 HIPK2, which mediates p53 phosphorylation and ultraviolet (UV)-induced apoptosis 24,25 (for details, see section on 'Regulation of p53 activity in PML-NBs') was found to interact with TRADD when overexpressed in 293T cells.…”

Section: Hipksmentioning

confidence: 99%

Body language: the function of PML nuclear bodies in apoptosis regulation

2003

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Promyelocytic leukaemia (PML) nuclear bodies (NBs) are macromolecular nuclear domains present in virtually every mammalian cell. PML nuclear bodies (PML-NBs) were functionally linked to various fundamental cellular processes, including transcriptional control, tumour suppression and apoptosis regulation. Supporting the important function of PML and its associated NBs in apoptosis regulation, several apoptotic regulators localise to PML-NBs, and cells from PMLdeficient mice show severe apoptotic defects, including induction of genotoxic stress and death receptor CD95 (Fas/ APO-1) activation. Based on the current literature, we hypothesise that PML-NBs regulate apoptosis through different molecular mechanisms, on the one hand by acting as macromolecular scaffolds for recruitment and post-translational modification of the apoptotic key regulator p53, and on the other by regulating the subcellular bioavailability and quality of some apoptotic signal transducers.

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“…The same clone has recently been isolated independently and the corresponding protein (HIPK) reported to act as a corepressor for homeodomain transcription factors (Kim et al, 1998). If ATFa also interacts with HIPK in mammalian cells, this would be an additional example of a negative regulatory factor that is tethered to the DNA via ATFa.…”

Section: Transcriptional Repression By Mammentioning

confidence: 99%

A murine ATFa-associated factor with transcriptional repressing activity

et al. 2000

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The ATFa proteins, which are members of the CREB/ ATF family of transcription factors, have previously been shown to interact with the adenovirus E1a oncoprotein and to mediate its transcriptional activity; they heterodimerize with Jun, Fos or related transcription factors, possibly altering their DNA-binding speci®city; they also stably bind JNK2, a stress-induced protein kinase. Here we report the identi®cation and characterization of a novel protein isolated in a yeast two-hybrid screen using the N-terminal half of ATFa as a bait. This 1306-residue protein (mAM, for mouse ATFa-associated Modulator) is rather acidic (pHi 4.5) and contains high proportions of Ser/Thr (21%) and Pro (11%) residues. It colocalizes and interacts with ATFa in mammalian cells, contains a bipartite nuclear localization signal and possesses an ATPase activity. Transfection experiments show that mAM is able to downregulate transcriptional activity, in an ATPase-independent manner. Our results indicate that mAM interacts with several components of the basal transcription machinery (TFIIE and TFIIH), including RNAPII itself. Together, these ®ndings suggest that mAM may be involved in the ®ne-tuning of ATFaregulated gene expression, by interfering with the assembly or stability of speci®c preinitiation transcription complexes.

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Homeodomain-interacting Protein Kinases, a Novel Family of Co-repressors for Homeodomain Transcription Factors

Cited by 265 publications

References 25 publications

SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis

SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis

Body language: the function of PML nuclear bodies in apoptosis regulation

A murine ATFa-associated factor with transcriptional repressing activity

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