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An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity.
Mol Cell Biol. 2007 Apr; 27(7):2661-75.MC

Abstract

Tumor suppressor HIC1 (hypermethylated in cancer 1) is a gene that is essential for mammalian development, epigenetically silenced in many human tumors, and involved in a complex pathway regulating P53 tumor suppression activity. HIC1 encodes a sequence-specific transcriptional repressor containing five Krüppel-like C(2)H(2) zinc fingers and an N-terminal BTB/POZ repression domain. Here, we show that endogenous HIC1 is SUMOylated in vivo on a phylogenetically conserved lysine, K314, located in the central region which is a second repression domain. K314R mutation does not influence HIC1 subnuclear localization but significantly reduces its transcriptional repression potential, as does the mutation of the other conserved residue in the psiKXE consensus, E316A, or the overexpression of the deSUMOylase SSP3/SENP2. Furthermore, HIC1 is acetylated in vitro by P300/CBP. Strikingly, the K314R mutant is less acetylated than wild-type HIC1, suggesting that this lysine is a target for both SUMOylation and acetylation. We further show that HIC1 transcriptional repression activity is positively controlled by two types of deacetylases, SIRT1 and HDAC4, which increase the deacetylation and SUMOylation, respectively, of K314. Knockdown of endogenous SIRT1 by the transfection of short interfering RNA causes a significant loss of HIC1 SUMOylation. Thus, this dual-deacetylase complex induces either a phosphorylation-dependent acetylation-SUMOylation switch through a psiKXEXXSP motif, as previously shown for MEF2, or a phosphorylation-independent switch through a psiKXEP motif, as shown here for HIC1, since P317A mutation severely impairs HIC1 acetylation. Finally, our results demonstrate that HIC1 is a target of the class III deacetylase SIRT1 and identify a new posttranslational modification step in the P53-HIC1-SIRT1 regulatory loop.

Authors+Show Affiliations

CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, 1 Rue Calmette, BP 447, 59017 Lille Cedex, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17283066

Citation

Stankovic-Valentin, Nicolas, et al. "An acetylation/deacetylation-SUMOylation Switch Through a Phylogenetically Conserved psiKXEP Motif in the Tumor Suppressor HIC1 Regulates Transcriptional Repression Activity." Molecular and Cellular Biology, vol. 27, no. 7, 2007, pp. 2661-75.
Stankovic-Valentin N, Deltour S, Seeler J, et al. An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity. Mol Cell Biol. 2007;27(7):2661-75.
Stankovic-Valentin, N., Deltour, S., Seeler, J., Pinte, S., Vergoten, G., Guérardel, C., Dejean, A., & Leprince, D. (2007). An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity. Molecular and Cellular Biology, 27(7), 2661-75.
Stankovic-Valentin N, et al. An acetylation/deacetylation-SUMOylation Switch Through a Phylogenetically Conserved psiKXEP Motif in the Tumor Suppressor HIC1 Regulates Transcriptional Repression Activity. Mol Cell Biol. 2007;27(7):2661-75. PubMed PMID: 17283066.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity. AU - Stankovic-Valentin,Nicolas, AU - Deltour,Sophie, AU - Seeler,Jacob, AU - Pinte,Sébastien, AU - Vergoten,Gérard, AU - Guérardel,Cateline, AU - Dejean,Anne, AU - Leprince,Dominique, Y1 - 2007/02/05/ PY - 2007/2/7/pubmed PY - 2007/5/1/medline PY - 2007/2/7/entrez SP - 2661 EP - 75 JF - Molecular and cellular biology JO - Mol. Cell. Biol. VL - 27 IS - 7 N2 - Tumor suppressor HIC1 (hypermethylated in cancer 1) is a gene that is essential for mammalian development, epigenetically silenced in many human tumors, and involved in a complex pathway regulating P53 tumor suppression activity. HIC1 encodes a sequence-specific transcriptional repressor containing five Krüppel-like C(2)H(2) zinc fingers and an N-terminal BTB/POZ repression domain. Here, we show that endogenous HIC1 is SUMOylated in vivo on a phylogenetically conserved lysine, K314, located in the central region which is a second repression domain. K314R mutation does not influence HIC1 subnuclear localization but significantly reduces its transcriptional repression potential, as does the mutation of the other conserved residue in the psiKXE consensus, E316A, or the overexpression of the deSUMOylase SSP3/SENP2. Furthermore, HIC1 is acetylated in vitro by P300/CBP. Strikingly, the K314R mutant is less acetylated than wild-type HIC1, suggesting that this lysine is a target for both SUMOylation and acetylation. We further show that HIC1 transcriptional repression activity is positively controlled by two types of deacetylases, SIRT1 and HDAC4, which increase the deacetylation and SUMOylation, respectively, of K314. Knockdown of endogenous SIRT1 by the transfection of short interfering RNA causes a significant loss of HIC1 SUMOylation. Thus, this dual-deacetylase complex induces either a phosphorylation-dependent acetylation-SUMOylation switch through a psiKXEXXSP motif, as previously shown for MEF2, or a phosphorylation-independent switch through a psiKXEP motif, as shown here for HIC1, since P317A mutation severely impairs HIC1 acetylation. Finally, our results demonstrate that HIC1 is a target of the class III deacetylase SIRT1 and identify a new posttranslational modification step in the P53-HIC1-SIRT1 regulatory loop. SN - 0270-7306 UR - https://www.unboundmedicine.com/medline/citation/17283066/An_acetylation/deacetylation_SUMOylation_switch_through_a_phylogenetically_conserved_psiKXEP_motif_in_the_tumor_suppressor_HIC1_regulates_transcriptional_repression_activity_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=17283066 DB - PRIME DP - Unbound Medicine ER -