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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>
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>
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>
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>
Core Binding Factor β of Osteoblasts Maintains Cortical Bone Mass Via Stabilization of Runx2 in Mice
Lim, Kyung-Eun,Park, Na-Rae,Che, Xiangguo,Han, Min-Su,Jeong, Jae-Hwan,Kim, Shin-Yoon,Park, Clara Yongjoo,Akiyama, Haruhiko,Kim, Jung-Eun,Ryoo, Hyun-Mo,Stein, Janet L,Lian, Jane B,Stein, Gary S,Choi, J Wiley (John WileySons) 2015 Journal of bone and mineral research Vol.30 No.10