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Han, Min-Su,Kim, Hyo-Jin,Wee, Hee-Jun,Lim, Kyung-Eun,Park, Na-Rae,Bae, Suk-Chul,van Wijnen, Andre J.,Stein, Janet L.,Lian, Jane B.,Stein, Gary S.,Choi, Je-Yong Wiley Subscription Services, Inc., A Wiley Company 2010 Journal of cellular biochemistry Vol.110 No.1
<P>Cleidocranial dysplasia (CCD) is caused by haploinsufficiency in RUNX2 function. We have previously identified a series of RUNX2 mutations in Korean CCD patients, including a novel R131G missense mutation in the Runt-homology domain. Here, we examine the functional consequences of the RUNX2<SUP>R131G</SUP> mutation, which could potentially affect DNA binding, nuclear localization signal, and/or heterodimerization with core-binding factor-β (CBF-β). Immunofluorescence microscopy and western blot analysis with subcellular fractions show that RUNX2<SUP>R131G</SUP> is localized in the nucleus. Immunoprecipitation analysis reveals that heterodimerization with CBF-β is retained. However, precipitation assays with biotinylated oligonucleotides and reporter gene assays with RUNX2 responsive promoters together reveal that DNA-binding activity and consequently the transactivation of potential of RUNX2<SUP>R131G</SUP> is abrogated. We conclude that loss of DNA binding, but not nuclear localization or CBF-β heterodimerization, causes RUNX2 haploinsufficiency in patients with the RUNX2<SUP>R131G</SUP> mutation. Retention of specific functions including nuclear localization and binding to CBF-β of the RUNX2<SUP>R131G</SUP> mutation may render the mutant protein an effective competitor that interferes with wild-type function. J. Cell. Biochem. 110: 97–103, 2010. © 2010 Wiley-Liss, Inc.</P>
Kim, Hyo-Jin,Nam, Soon-Hyeun,Kim, Hyun-Jung,Park, Hyo-Sang,Ryoo, Hyun-Mo,Kim, Shin-Yoon,Cho, Tae-Joon,Kim, Seung-Gon,Bae, Suk-Chul,Kim, In-San,Stein, Janet L.,van Wijnen, Andre J.,Stein, Gary S.,Lian, Liss 2006 Journal of Cellular Physiology Vol.207 No.1
<P>Cleidocranial dysplasia (CCD) is an autosomal dominant disorder caused by haploinsufficiency of the RUNX2 gene. In this study, we analyzed by direct sequencing RUNX2 mutations from eleven CCD patients. Four of seven mutations were novel: two nonsense mutations resulted in a translational stop at codon 50 (Q50X) and 112 (E112X); a missense mutation converted arginine to glycine at codon 131 (R131G); and an exon 1 splice donor site mutation (donor splice site GT/AT, IVS1 + 1G > A) at exon 1–intron junction resulted in the deletion of QA stretch contained in exon 1 of RUNX2. We focused on the functional analysis of the IVS1 + 1G > A mutation. A full-length cDNA of this mutation was cloned (RUNX2Δe1) and expressed in Chinese hamster ovary (CHO) and HeLa cells. Functional analysis of RUNX2Δe1 was performed with respect to protein stability, nuclear localization, DNA binding, and transactivation activity of a downstream RUNX2 target gene. Protein stability of RUNX2Δe1 is similar to wild-type RUNX2 as determined by Western blot analysis. Subcellular localization of RUNX2Δe1, assessed by in situ immunofluorescent staining, was observed with partial retention in both the nucleus and cytoplasm. This finding is in contrast to RUNX2 wild-type, which is detected exclusively in the nucleus. DNA binding activity was also compromised by the RUNX2Δe1 in gel shift assay. Finally, RUNX2Δe1 blocked transactivation of the osteocalcin gene determined by transient transfection assay. Our findings demonstrate for the first time that the CCD phenotype can be caused by a splice site mutation, which results in the deletion of N-terminus amino acids containing the QA stretch in RUNX2 that contains a previously unidentified second nuclear localization signal (NLS). We postulate that the QA sequence unique to RUNX2 contributes to a competent structure of RUNX2 that is required for nuclear localization, DNA binding, and transactivation function. J. Cell. Physiol. 207: 114–122, 2006. © 2005 Wiley-Liss, Inc.</P>
Stein, Gary S.,Zaidi, Sayyed K.,Stein, Janet L.,Lian, Jane B.,van Wijnen, Andre J.,Montecino, Martin,Young, Daniel W.,Javed, Amjad,Pratap, Jitesh,Choi, Je-Yong,Ali, Syed A.,Pande, Sandhya,Hassan, Moha Canadian Science Publishing 2009 Biochemistry and cell biology Vol.87 No.1
<P> Epigenetic control is required to maintain competency for the activation and suppression of genes during cell division. The association between regulatory proteins and target gene loci during mitosis is a parameter of the epigenetic control that sustains the transcriptional regulatory machinery that perpetuates gene-expression signatures in progeny cells. The mitotic retention of phenotypic regulatory factors with cell cycle, cell fate, and tissue-specific genes supports the coordinated control that governs the proliferation and differentiation of cell fate and lineage commitment. </P>
Stein, Gary S.,Zaidi, Sayyed K.,Stein, Janet L.,Lian, Jane B.,Van Wijnen, Andre J.,Montecino, Martin,Young, Daniel W.,Javed, Amjad,Pratap, Jitesh,Choi, Je-Yong,Ali, Syed A.,Pande, Sandhya,Hassan, Moha Wiley (Blackwell Publishing) 2009 Annals of the New York Academy of Sciences Vol.1155 No.1
<P>There is growing awareness that the fidelity of gene expression necessitates coordination of transcription factor metabolism and organization of genes and regulatory proteins within the three-dimensional context of nuclear architecture. The regulatory machinery that governs genetic and epigenetic control of gene expression is compartmentalized in nuclear microenvironments. Temporal and spatial parameters of regulatory complex organization and assembly are functionally linked to biological control and are compromised with the onset and progression of tumorigenesis. High throughput imaging of cells, tissues, and tumors, including live cell analysis, is expanding research's capabilities toward translating components of nuclear organization into novel strategies for cancer diagnosis and therapy.</P>
Cho, Young-Dan,Yoon, Won-Joon,Kim, Woo-Jin,Woo, Kyung-Mi,Baek, Jeong-Hwa,Lee, Gene,Ku, Young,van Wijnen, Andre J.,Ryoo, Hyun-Mo American Society for Biochemistry and Molecular Bi 2014 The Journal of biological chemistry Vol.289 No.29
<P>Mesenchymal cells alter and retain their phenotype during skeletal development through activation or suppression of signaling pathways. For example, we have shown that Wnt3a only stimulates osteoblast differentiation in cells with intrinsic osteogenic potential (<I>e.g.</I> MC3T3-E1 pre-osteoblasts) and not in fat cell precursors or fibroblasts (3T3-L1 pre-adipocytes or NIH3T3 fibroblasts, respectively). Wnt3a promotes osteogenesis in part by stimulating autocrine production of the osteoinductive ligand Bmp2. Here, we show that the promoter regions of the genes for <I>Bmp2</I> and the osteoblast marker <I>Alp</I> are epigenetically locked to prevent their expression in nonosteogenic cells. Both genes have conserved CpG islands that exhibit increased CpG methylation, as well as decreased acetylation and increased methylation of histone H3 lysine 9 (H3-K9) specifically in nonosteogenic cells. Treatment of pre-adipocytes or fibroblasts with the CpG-demethylating agent 5′-aza-2′-deoxycytidine or the histone deacetylase inhibitor trichostatin-A renders <I>Bmp2</I> and <I>Alp</I> responsive to Wnt3a. Hence, drug-induced epigenetic activation of <I>Bmp2</I> gene expression contributes to Wnt3a-mediated direct trans-differentiation of pre-adipocytes or fibroblasts into osteoblasts. We propose that direct conversion of nonosteogenic cells into osteoblastic cell types without inducing pluripotency may improve prospects for novel epigenetic therapies to treat skeletal afflictions.</P>
The TGFβ→TAK1→LATS→YAP1 Pathway Regulates the Spatiotemporal Dynamics of YAP1
Min-Kyu Kim,Sang-Hyun Han,Tae-Geun Park,Soo-Hyun Song,Ja-Youl Lee,이유섭,Seo-Yeong Yoo,Xin-Zi Chi,김응국,Ju-Won Jang,임대식,Andre J. van Wijnen,Jung-Won Lee,배석철 한국분자세포생물학회 2023 Molecules and cells Vol.46 No.10
The Hippo kinase cascade functions as a central hub that relays input from the “outside world” of the cell and translates it into specific cellular responses by regulating the activity of Yes-associated protein 1 (YAP1). How Hippo translates input from the extracellular signals into specific intracellular responses remains unclear. Here, we show that transforming growth factor β (TGFβ)-activated TAK1 activates LATS1/2, which then phosphorylates YAP1. Phosphorylated YAP1 (p-YAP1) associates with RUNX3, but not with TEAD4, to form a TGFβ-stimulated restriction (R)-point-associated complex which activates target chromatin loci in the nucleus. Soon after, p-YAP1 is exported to the cytoplasm. Attenuation of TGFβ signaling results in re-localization of unphosphorylated YAP1 to the nucleus, where it forms a YAP1/TEAD4/SMAD3/AP1/p300 complex. The TGFβ-stimulated spatiotemporal dynamics of YAP1 are abrogated in many cancer cells. These results identify a new pathway that integrates TGFβ signals and the Hippo pathway (TGFβ→TAK1→LATS1/2→YAP1 cascade) with a novel dynamic nuclear role for p-YAP1.
Jeong, Jae-Hwan,Jung, Youn-Kwan,Kim, Hyo-Jin,Jin, Jung-Sook,Kim, Hyun-Nam,Kang, Sang-Min,Kim, Shin-Yoon,van Wijnen, Andre J.,Stein, Janet L.,Lian, Jane B.,Stein, Gary S.,Kato, Shigeaki,Choi, Je-Yong American Society for Microbiology 2010 Molecular and cellular biology Vol.30 No.10
<B>ABSTRACT</B><P>The essential osteoblast-related transcription factor Runx2 and the female steroid hormone estrogen are known to play pivotal roles in bone homeostasis; however, the functional interaction between Runx2- and estrogen-mediated signaling in skeletal tissues is minimally understood. Here we provide evidence that aromatase (CYP19), a rate-limiting enzyme responsible for estrogen biosynthesis in mammals, is transcriptionally regulated by Runx2. Consistent with the presence of multiple Runx2 binding sites, the binding of Runx2 to the aromatase promoter was demonstrated <I>in vitro</I> and confirmed <I>in vivo</I> by chromatin immunoprecipitation assays. The bone-specific aromatase promoter is activated by Runx2, and endogenous aromatase gene expression is upregulated by Runx2 overexpression, establishing the aromatase gene as a target of Runx2. The biological significance of the Runx2 transcriptional control of the aromatase gene is reflected by the enhanced estrogen biosynthesis in response to Runx2 in cultured cells. Reduced <I>in vivo</I> expression of skeletal aromatase gene and low bone mineral density are evident in Runx2 mutant mice. Collectively, these findings uncover a novel link between Runx2-mediated osteoblastogenic processes and the osteoblast-mediated biosynthesis of estrogen as an osteoprotective steroid hormone.</P>