SUMO Interaction Motifs in Sizn1 Are Required for Promyelocytic Leukemia Protein Nuclear Body Localization and for Transcriptional Activation

Department of Pathology, The Children's Hospital of Philadelphia, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2009; 284(29):19592-600. DOI: 10.1074/jbc.M109.010181
Source: PubMed


Mutations in Sizn1 (Zcchc12), a novel transcriptional co-activator in the BMP signaling pathway, are associated with X-linked mental retardation. Previously, we demonstrated that Sizn1 positively modulates the BMP signal by interacting with Smad family members and cAMP-responsive element-binding protein-binding protein. To further define the molecular basis of Sizn1 function, we have explored its subcellular localization and generated various deletion mutants to carry out domain analyses. Here, we report that Sizn1 localizes to promyelocytic leukemia protein nuclear bodies (PML-NBs). Sizn1 deletion mutants that disrupt the MA homologous domain or the middle region fail to target to the PML-NB. We show that two SUMO interaction motifs (SIMs) in Sizn1 can bind to SUMO and govern SUMO conjugation to Sizn1 in the absence of the consensus motif for SUMO attachment. Interestingly, the SIM mutant Sizn1 localizes to nuclear bodies, but not to PML-NBs. Thus, SIMs mediate the localization of Sizn1 to PML-NB. Interestingly, mutations in SIM sequences and deletion of the MA homologous domain also affected the transcriptional co-activation function of a Sizn1. Taken together, our data indicate that the SIMs in Sizn1 are required for its PML-NB localization and for the full transcriptional co-activation function in BMP signaling.

Download full-text


Available from: Ginam Cho, Nov 13, 2015
  • Source
    • "DEC1 is predominantly localized in the nucleus, but can also be found in the cytoplasm. SUMOylation is known to affect the subcellular localization of a protein [32], [33]. To test whether SUMOylation influence the nucleolar translocation of DEC1, MCF-7 cells were transfected with HA-tagged wild-type DEC1 or its mutant 2K/2R and then subjected to nucleo-cytoplasmic separation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Differentiated embryo-chondrocyte expressed gene 1 (DEC1, also known as sharp2, stra13, or BHLHB2) is a mammalian basic helix-loop-helix protein that is involved in many aspects of gene regulation through acting as a transcription factor. Changes in DEC1 expression levels have been implicated in the development of cancers. Using COS-7 cell, we showed that DEC1 can be modified by the small ubiquitin-like modifiers, SUMO1, 2 and 3. Two major SUMOylation sites (K(159) and K(279)) were identified in the C-terminal domain of DEC1. Substitution of either K(159) or K(279) with arginine reduced DEC1 SUMOylation, but substitution of both K(159) and K(279) abolished SUMOylation, and more protein appeared to be retained in the cytoplasm compared to wild-type DEC1. The expression of DEC1 was up-regulated after serum starvation as previously reported, but at the same time, serum starvation also led to more SUMOylation of DEC1. In MCF-7 cells SUMOylation also stabilized DEC1 through inhibiting its ubiquitination. Moreover, SUMOylation of DEC1 promoted its repression of CLOCK/BMAL1-mediated transcriptional activity through recruitment of histone deacetylase1. These findings suggested that posttranslational modification of DEC1 in the form of SUMOylation may serve as a key factor that regulates the function of DEC1 in vivo.
    PLoS ONE 08/2011; 6(8):e23046. DOI:10.1371/journal.pone.0023046 · 3.23 Impact Factor
  • Source
    • "In summary, Sizn1 shows a spatially and temporally dynamic expression pattern through development. We have confirmed the subcellular localization in the nucleus of cells (Cho et al., 2009). As reported previously, Sizn1 is expressed in ventral forebrain including the septum, striatum and amygdala (Cho et al., 2008b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sizn1 (Zcchc12) is a transcriptional co-activator that positively modulates bone morphogenic protein (BMP) signaling through its interaction with Smad family members and CBP. We have demonstrated a role for Sizn1 in basal forebrain cholinergic neuron specific gene expression. Furthermore, mutations in SIZN1 have been associated with X-linked mental retardation. Given the defined role of SIZN1 in mental retardation, knowing its complete forebrain expression pattern is essential to further elucidating its role in cognition. To better define the dynamic expression pattern of Sizn1 during forebrain development, we investigated its expression in mouse brain development from embryonic day 8.0 (E8.0) to adult. We found that Sizn1 is primarily restricted to the ventral forebrain including the medial ganglionic eminence, the septum, amygdala, and striatum. In addition, Sizn1 expression is detected in the cortical hem and pallial-subpallial boundary (PSB; anti-hem); both sources of Cajal-Retzius cells. Sizn1 expression in the dorsal forebrain is restricted to a subset of cells in the marginal zone that also express Reln, indicative of Cajal-Retzius cells. These data provide novel information on brain regions and cell types that express Sizn1, facilitating further investigations into the function of Sizn1 in both development and the pathogenesis of mental retardation.
    Gene Expression Patterns 03/2011; 11(3-4):216-20. DOI:10.1016/j.gep.2010.12.005 · 1.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this paper we report on the field emission properties of single crystal diamond emitters, which are boron-doped emitters, ion implanted emitters and phosphorus-doped emitters.
    Vacuum Microelectronics Conference, 2003. Technical Digest of the 16th International; 08/2003
Show more