Menin Suppresses Osteoblast Differentiation by Antagonizing the AP-1 Factor, JunD

Naito, Junko; Kaji, Hiroshi; Sowa, Hideaki; Hendy, Geoffrey N.; Sugimoto, Toshitsugu; Chihara, Kazuo

doi:10.1074/jbc.m408143200

Cited by 57 publications

(48 citation statements)

References 46 publications

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“…These results suggest that JunD and menin generally function in combination when they exert their biological effects in vivo. A recent study demonstrated that this is the case in bone development, wherein menin and JunD function as a complex in the regulation of osteoblast differentiation (Naito et al 2005). The present results of ours have reinforced this notion.…”

Section: Discussionmentioning

confidence: 99%

Coexpression of Menin and JunD during the Duct Cell Differentiation in Mouse Submandibular Gland

Hipkaeo

Sakulsak

Wakayama

et al. 2008

Tohoku J. Exp. Med.

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In the submandibular gland (SMG) of mice, a duct portion called the granular convoluted tubule (GCT) is developed preferentially in males with puberty. This sexual dimorphism is androgen-dependent, but the underlying molecular mechanisms are unclear. We have demonstrated that the expression of a transcription factor JunD is regulated in association with the androgen-induced differentiation of GCT cells from striated duct (SD) cells. Menin, a nuclear protein encoded by the MEN1 tumor-suppressor gene, is known to bind JunD, thereby inhibiting its activity. In the present study, we examined the expression of menin in the mouse SMG by use of Northern blotting, Western blotting, and immunohistochemistry. Immunoreactivity for menin was higher in the female than male gland, and localized to the nuclei of intercalated duct cells and a subpopulation of SD cells. In contrast, GCT cells in males appeared negative for menin. The levels of menin in the SMG were increased with castration in males and decreased by repeated administration of testosterone to females or to castrated males. After a single administration of testosterone to females, many SD cells newly gained nuclear menin, which was lost as the cells converted to GCT cells by 48 hrs. These patterns of the expression and localization of menin were quite similar to those of JunD. Furthermore, the coimmunoprecipitation analysis of the SMG homogenates indicated that menin binds JunD in vivo. The present study suggests that the JunD-menin complex plays signifi cant roles in the androgen-dependent differentiation of the duct system in the mouse SMG.

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Section: Discussionmentioning

confidence: 99%

Coexpression of Menin and JunD during the Duct Cell Differentiation in Mouse Submandibular Gland

Hipkaeo

Sakulsak

Wakayama

et al. 2008

Tohoku J. Exp. Med.

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“…JunD is coexpressed at high levels with Fra-2 in fully differentiated osteoblasts (McCabe et al, 1996). Loss of function of the negative JunD regulator, MEN1, correlates with increased JunD expression in osteoblasts and upregulation of osteoblast markers Naito et al, 2005). A clue that JunD acts after the commitment of the cells to the osteoblast lineage is the observation that JunD regulates critical osteoblast genes, although junDÀ/À mice have not been reported to demonstrate severe skeletal deformities characteristic of other osteoblast lineage genes.…”

Section: Jund Negatively Regulates Ras-mediated Transformationmentioning

confidence: 99%

“…The regulatory domain motif is well conserved in c-Jun and JunB, and was determined to have a negative effect on transcription (Kim et al, 2002). Downregulation of MEN1 in osteoblasts increases JunD transcriptional activity via the junD transcription autoregulatory loop, which in turn increases steady-state JunD protein level (Naito et al, 2005). Since MEN1 interaction is mediated by the JunD N-terminus, DJunD does not bind MEN1 and is not susceptible to MEN1 repression (Yazgan and Pfarr, 2002).…”

Section: Men1 Represses Jund Activity By Two Mechanismsmentioning

confidence: 99%

“…As highlighted in Figure 1, MEN1 interaction represses JunD transcriptional activity by inhibition of JunD phosphorylation by JNK and ERK2 (Agarwal et al, 1999;Gobl et al, 1999Gobl et al, , 2002Naito et al, 2005), and also by recruitment of the mSin3A-histone deacetylase (HDAC) complex (Kim et al, 2003). This effect of MEN1 on JunD function involves changes in chromatin structure in the promoter regions of JunD-MEN1 transcriptional targets.…”

Section: Men1 Represses Jund Activity By Two Mechanismsmentioning

confidence: 99%

“…JunD positively regulates the expression of osteoblast-specific proteins, type I collagen, osteocalcin and alkaline phosphatase (Table 1; Naito et al, 2005;Akhouayri and St Arnaud, 2007). JunD is coexpressed at high levels with Fra-2 in fully differentiated osteoblasts (McCabe et al, 1996).…”

Section: Jund Negatively Regulates Ras-mediated Transformationmentioning

confidence: 99%

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Multiple facets of junD gene expression are atypical among AP-1 family members

et al. 2008

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JunD is a versatile AP-1 transcription factor that can activate or repress a diverse collection of target genes. Precise control of junD expression and JunD proteinprotein interactions modulate tumor angiogenesis, cellular differentiation, proliferation and apoptosis. Molecular and clinical knowledge of two decades has revealed that precise JunD activity is elaborated by interrelated layers of constitutive transcriptional control, complex post-transcriptional regulation and a collection of post-translational modifications and protein-protein interactions. The stakes are high, as inappropriate JunD activity contributes to neoplastic, metabolic and viral diseases. This article deconvolutes multiple layers of control that safeguard junD gene expression and functional activity. The activity of JunD in transcriptional activation and repression is integrated into a regulatory network by which JunD exerts a pivotal role in cellular growth control. Our discussion of the JunD regulatory network integrates important open issues and posits new therapeutic targets for the neoplastic, metabolic and viral diseases associated with JunD/AP-1 expression.

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JunD suppresses bone formation and contributes to low bone mass induced by estrogen depletion

Kawamata

Izu

Yokoyama

et al. 2008

J of Cellular Biochemistry

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JunD is an activator protein-1 (AP-1) component though its function in skeletal system is still not fully understood. To elucidate the role of JunD in the regulation of bone metabolism, we analyzed JunD-deficient mice. JunD deficiency significantly increased bone mass and trabecular number. This bone mass enhancement was due to JunD deficiency-induced increase in bone formation activities in vivo. Such augmentation of bone formation was associated with simultaneous increase in bone resorption while the former was dominant over the latter as accumulation of bone mass occurred in JunD-deficient mice. In a pathological condition relevant to postmenopausal osteoporosis, ovariectomy reduced bone mass in wild type (WT) mice as known before. Interestingly, JunD deficiency suppressed ovariectomy-induced increase in bone resorption and kept high bone mass. In addition, JunD deficiency also enhanced new bone formation after bone marrow ablation. Examination of molecular bases for these observations revealed that JunD deficiency enhanced expression levels of c-jun, fra-1, and fra-2 in bone in conjunction with elevated expression levels of runx2, type I collagen, and osteocalcin. Thus, JunD is involved in estrogen depletion-induced osteopenia via its action to suppress bone formation and to enhance bone resorption.

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Menin Suppresses Osteoblast Differentiation by Antagonizing the AP-1 Factor, JunD

Cited by 57 publications

References 46 publications

Coexpression of Menin and JunD during the Duct Cell Differentiation in Mouse Submandibular Gland

Coexpression of Menin and JunD during the Duct Cell Differentiation in Mouse Submandibular Gland

Multiple facets of junD gene expression are atypical among AP-1 family members

JunD suppresses bone formation and contributes to low bone mass induced by estrogen depletion

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