CCAAT/Enhancer-binding Proteins (C/EBP) β and δ Activate Osteocalcin Gene Transcription and Synergize with Runx2 at the C/EBP Element to Regulate Bone-specific Expression

Gutiérrez, Soraya E.; Javed, Amjad; Tennant, Daniel K.; Rees, Monique van; Montecino, Martín; Stein, Gary S.; Lian, Jane B.

doi:10.1074/jbc.m106611200

Cited by 237 publications

(256 citation statements)

References 62 publications

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“…This is reaffirmed by recent work demonstrating that mice overexpressing a dominant negative isoform of C/EBP β, p20C/EBP β, LIP, under the control of the type I collagen promoter exhibit osteopenia and a phenotype similar to the one we report in CHOP overexpressing mice [45]. These in vivo findings are in agreement with observations demonstrating that, by interacting with Runx-2, C/EBP β can induce osteocalcin transcription and can promote osteoblast differentiation [6,7]. Consequently, the overexpression of a dominant negative C/EBP β or of CHOP would prevent C/EBP β-DNA interactions or would result in sequestration of C/EBP β and as a consequence impaired osteoblastic function.…”

Section: Discussionsupporting

confidence: 91%

CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia

Pereira

Stadmeyer

Smith

et al. 2007

Bone

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CCAAT enhancer binding protein (C/EBP) homologous protein (CHOP), is a member of the C/EBP family of nuclear proteins and plays a role in osteoblastic and adipocytic cell differentiation. CHOP is necessary for normal bone formation, but the consequences of its overexpression in vivo are not known. To investigate the direct actions of CHOP on bone remodeling in vivo, we generated transgenic mice overexpressing CHOP under the control of the human osteocalcin promoter. CHOP transgenics exhibited normal weight and reduced bone mineral density. Static and dynamic femoral bone histomorphometry revealed that CHOP overexpression caused reduced trabecular bone volume, secondary to decreased bone formation rates. One of 2 lines displayed a decrease in the number of osteoblasts, but in vivo bromodeoxyuridine labeling demonstrated that CHOP overexpression did not have an effect on osteoblastic cell replication. The decreased osteoblast cell number was accounted by an increase in apoptosis, as determined by DNA fragmentation measured by transferase-mediated digoxigenin-deoxyuridine triphosphate (dUTP) in situ nick-end labeling (TUNEL) reaction. In conclusion, transgenic mice overexpressing CHOP in the bone microenvironment have impaired osteoblastic function leading to osteopenia.

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Section: Discussionsupporting

confidence: 91%

CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia

Pereira

Stadmeyer

Smith

et al. 2007

Bone

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“…The N terminus binds specific DNA sequences, whereas the C-terminal domain interacts with coregulatory factors and associates with the nuclear matrix (10)(11)(12)(13). During tissue differentiation, Runx proteins form stage-specific complexes with subsets of coactivators (14)(15)(16), corepressors (17)(18)(19), and factors that are end points of key signaling cascades (20,21). These multimeric complexes are organized in punctuate subnuclear foci that constitute nuclear microenvironments (22).…”

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confidence: 99%

Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo

Javed

Barnes

Pratap

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Runx transcription factors comprise a family of proteins that are essential for organogenesis. A unique nuclear matrix-targeting signal in the C terminus directs these factors to their appropriate subnuclear domains. At these sites, they interact with coregulatory proteins and target genes. We have previously shown that aberrant expression of the Runx2 DNA binding domain in metastatic breast cancer cells can prevent production of osteolytic lesions in bone. Here, we show that proper Runx2 subnuclear targeting is required for osteolysis. We have identified point mutations of the Runx2 nuclear matrix-targeting signal sequence that impair its targeting to nuclear matrix sites. These mutations block the invasive and osteolytic properties of MDA-MB-231 breast cancer cells in vivo. Cell lines expressing this Runx2 mutant protein inhibit the osteogenic properties of bone marrow stromal cells in coculture assays. The mutant breast cancer cells also exhibit reduced invasiveness in vitro and do not express genes involved in invasion and angiogenesis (VEGF and MMP13). Our findings suggest that fidelity of Runx2 intranuclear organization is necessary for expression of target genes that mediate the osteolytic activity of metastatic breast cancer cells.gene expression ͉ intranuclear organization ͉ nuclear matrix R unx (AML͞CBFA͞PEBP2) transcription factors are tissuespecific regulatory proteins that are involved in the control of hematopoiesis (Runx1͞AML1), osteogenesis (Runx2͞ AML3), and neural and gastrointestinal cell differentiation (Runx3͞AML2) (1-3). Translocations or mutations of Runx1 results in leukemogenesis (4), whereas mutations of Runx2 and Runx3 lead to skeletal disease (5) and stomach cancer (3), respectively. The Runx transcription factors function as scaffolds for interaction with various coregulatory proteins. These complexes interact in a combinatorial fashion to regulate gene expression. Furthermore, Runx proteins are focally localized within the nucleus. The subnuclear localization of Runx proteins requires at least two trafficking signals; one signal supports nuclear import (nuclear localization signals) and the other signal is required for residency in nuclear matrix-associated regulatory domains (nuclear matrix-targeting signal; NMTS) (6-9). The role of Runx proteins in both gene expression and nuclear structure is a reflection of their modular organization. The N terminus binds specific DNA sequences, whereas the C-terminal domain interacts with coregulatory factors and associates with the nuclear matrix (10-13). During tissue differentiation, Runx proteins form stage-specific complexes with subsets of coactivators (14-16), corepressors (17-19), and factors that are end points of key signaling cascades (20,21). These multimeric complexes are organized in punctuate subnuclear foci that constitute nuclear microenvironments (22).The critical role of Runx2 in osteogenesis has provided a model for investigating the importance of subnuclear localization for tissue differentiation. Mice homozygous for Runx2 ...

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“…A number of transcription factors that bind to specific regions of the osteocalcin gene promoter have also been identified. These factors include AP-1 family members (21,22), MSX-2/HOX 8.1 (23,24), , CCAAT/enhancer binding proteins (26), and RUNX2 (27), the osteoblast-specific product of the Cbfa1 gene. These factors play important roles in osteoblast and bone development and mediate the response of osteoblasts to the differentiation signals mentioned above.…”

mentioning

confidence: 99%

Parathyroid Hormone Induction of the Osteocalcin Gene

Jiang

Franceschi

Boules

et al. 2004

Journal of Biological Chemistry

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Parathyroid hormone (PTH) is an important peptide hormone regulator of bone formation and osteoblast activity. However, its mechanism of action in bone cells is largely unknown. This study examined the effect of PTH on mouse osteocalcin gene expression in MC3T3-E1 preosteoblastic cells and primary cultures of bone marrow stromal cells. PTH increased the levels of osteocalcin mRNA 4 -5-fold in both cell types. PTH also stimulated transcriptional activity of a 1.3-kb fragment of the mouse osteocalcin gene 2 (mOG2) promoter. Inhibitor studies revealed a requirement for protein kinase A, protein kinase C, and mitogen-activated protein kinase pathways in the PTH response. Deletion of the mOG2 promoter sequence from ؊1316 to ؊116 caused no loss in PTH responsiveness whereas deletion from ؊116 to ؊34 completely prevented PTH stimulation. Interestingly, this promoter region does not contain the RUNX2 binding site shown to be necessary for PTH responsiveness in other systems. Nuclear extracts from PTH-treated MC3T3-E1 cells exhibited increased binding to OSE1, a previously described osteoblast-specific enhancer in the mOG2 promoter. Furthermore, mutation of OSE1 in DNA transfection assays established the requirement for this element in the PTH response. Collectively, these studies establish that actions of PTH on the osteocalcin gene are mediated by multiple signaling pathways and require OSE1 and associated nuclear proteins.Parathyroid hormone (PTH) 1 is a major regulator of calcium homeostasis. PTH has catabolic and anabolic effects on osteoblasts and bone in vitro and in vivo, which depend on the temporal pattern of administration; continuous administration decreases bone mass whereas intermittent administration increases bone mass (1-4). PTH functions through the PTH-1 receptor, a G protein-coupled receptor that is expressed in osteoblasts (5-7). Binding of PTH to its receptor activates multiple intracellular signaling pathways that involve cyclic cAMP, inositol phosphates, intracellular Ca 2ϩ , protein kinases A and C (2), and the extracellular signal-regulated kinase/ mitogen-activated protein kinase (MAPK) pathway (8, 9).Osteocalcin (OCN), a 5700-dalton ␥-carboxyglutamic acidcontaining noncollagenous protein, is a major component of the bone extracellular matrix. Although the functions of OCN are poorly understood, gene deletion studies suggest possible functions in bone remodeling (10). The expression of OCN is regulated by a number of calcitropic hormones and growth factors including 1,25-dihydroxy vitamin D 3 (11-13), glucocorticoids (14, 15), PTH (16), bone morphogenetic proteins (17), basic fibroblast growth factor 2 (18), tumor necrosis factor-␣ (19), and transforming growth factor ␤ (20). A number of transcription factors that bind to specific regions of the osteocalcin gene promoter have also been identified. These factors include AP-1 family members (21, 22), MSX-2/HOX 8.1 (23, 24), DLX-5 (25), CCAAT/enhancer binding proteins (26), and RUNX2 (27), the osteoblast-specific product of the Cbfa1 gene. These f...

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CCAAT/Enhancer-binding Proteins (C/EBP) β and δ Activate Osteocalcin Gene Transcription and Synergize with Runx2 at the C/EBP Element to Regulate Bone-specific Expression

Cited by 237 publications

References 62 publications

CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia

CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia

Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo

Parathyroid Hormone Induction of the Osteocalcin Gene

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