Regulation of the Murine TRACP Gene Promoter

Cassady, A. I.; Luchin, A; Ostrowski, Michael C.; Hume, David

doi:10.1359/jbmr.2003.18.10.1901

Cited by 15 publications

(9 citation statements)

References 10 publications

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“…Using candidate approaches, multiple pigmentation-associated factors have been thus recognized, although it is noteworthy that factors other than MITF are undoubtedly important in their regulation as well, because the endogenous genes are not always predictably up-or down-regulated by modulation of Mitf expression alone (Gaggioli et al 2003). Other transcription factors of importance in the regulation of potential Mitf targets include CREB/ATF1, SOX10 (Jiao et al 2004;Ludwig et al 2004), Pax3 (as a negative regulator and potential media-tor of melanocyte stem cell maintenance) (Lang et al 2005), OTX2 in retinal pigment epithelium (MartinezMorales et al 2003), CBP and MAZR (in mast cells) (Ogihara et al 1999;Morii et al 2002), Pu.1 in osteoclast target genes Luchin et al 2001;Cassady et al 2003;So et al 2003;Partington et al 2004), Wnt/ LEF (Yasumoto et al 2002), and probably others as well.…”

Section: Transcriptional Targets Of Mitfmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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Section: Transcriptional Targets Of Mitfmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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“…RAW/C4 cells: a subclone of the RAW264.7 macrophagelike cell line (ATCC) (Cassady et al, 2003). RAW/C4 cells were cultured in Dulbecco's modified Eagle medium (DMEM) (Invitrogen) containing 5% heat-inactivated fetal calf serum (FCS) (Biowhittaker).…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

Microphthalmia transcription factor regulates the expression of the novel osteoclast factor GPNMB

Ripoll

Meadows

Raggatt

et al. 2008

Gene

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Microphthalmia transcription factor (MITF) regulates bone homeostasis by inducing expression of critical genes associated with osteoclast function. Gpnmb is a macrophage-enriched gene that has also been shown to be expressed in osteoblasts. Here, we have shown gpnmb to be highly induced in maturing murine osteoclasts. Microarray expression profile analysis identified gpnmb as a potential target of MITF in RAW264.7 cells, subclone C4 (RAW/C4), that overexpress this transcription factor. Electrophoretic mobility shift assays identified a MITF-binding site (M-box) in the gpnmb promoter that is conserved in different mammalian species. Anti-MITF antibody supershifted the DNA-MITF complex for the promoter site while MITF binding was abolished by mutation of this site. The gpnmb promoter was transactivated by co-expression of MITF in reporter gene assays while mutation of the gpnmb M-box prevented MITF transactivation. The induction of gpnmb expression during osteoclastogenesis was shown to exhibit similar kinetics to the known MITF targets, acp5 and clcn7. GPNMB expressed in RAW/C4 cells exhibited distinct subcellular distribution at different stages of osteoclast differentiation. At days 5 and 7, GPNMB protein co-localised with the osteoclast/macrophage lysosomal/endocytic marker MAC-3/LAMP-2, suggesting that GPNMB resides in the endocytic pathway of mature macrophages and is possibly targeted to the plasma membrane of bone-resorbing osteoclasts. The inclusion of gpnmb in the MITF regulon suggests a role for GPNMB in mature osteoclast function.

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“…RAW/C4 cells have an increased potential to form OCLs compared with the parent RAW264.7 cell line (45). MITF was cloned with a 3Ј V5 epitope tag in the pEF6 mammalian expression plasmid, under the control of the EF1␣ promoter (50).…”

Section: Exogenous Mitf Is Expressed In Stably Transfected Raw/c4mentioning

confidence: 99%

The Expression of Clcn7 and Ostm1 in Osteoclasts Is Coregulated by Microphthalmia Transcription Factor

Meadows

Sharma

Faulkner

et al. 2007

Journal of Biological Chemistry

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Microphthalmia transcription factor (MITF) regulates osteoclast function by controling the expression of genes, including tartrate-resistant acid phosphatase (TRAP) and cathepsin K in response to receptor activator of nuclear factor-B ligand (RANKL)-induced signaling. To identify novel MITF target genes, we have overexpressed MITF in the murine macrophage cell line RAW264.7 subclone 4 (RAW/C4) and examined the gene expression profile after sRANKL-stimulated osteoclastogenesis. Microarray analysis identified a set of genes superinduced by MITF overexpression, including Clcn7 (chloride channel 7) and Ostm1 (osteopetrosis-associated transmembrane protein 1). Using electrophoretic mobility shift assays, we identified two MITF-binding sites (M-boxes) in the Clcn7 promoter and a single M-box in the Ostm1 promoter. An anti-MITF antibody supershifted DNA-protein complexes for promoter sites in both genes, whereas MITF binding was abolished by mutation of these sites. The Clcn7 promoter was transactivated by coexpression of MITF in reporter gene assays. Mutation of one Clcn7 M-box prevented MITF transactivation, but mutation of the second MITF-binding site only reduced basal activity. Chromatin immunoprecipitation assays confirmed that the two Clcn7 MITF binding and responsive regions in vitro bind MITF in genomic DNA. The expression of Clcn7 is repressed in the dominant negative mutant Mitf mouse, mi/mi, indicating that the dysregulated bone resorption seen in these mice can be attributed in part to transcriptional repression of Clcn7. MITF regulation of the TRAP, cathepsin K, Clcn7, and Ostm1 genes, which are critical for osteoclast resorption, suggests that the role of MITF is more significant than previously perceived and that MITF may be a master regulator of osteoclast function and bone resorption.Bone-resorbing osteoclasts are multinucleated cells that are derived from the hematopoietic myeloid/monocyte lineage. Normal bone remodeling is controlled by the close interactions between osteoclasts and osteoblasts, the primary bone-synthesizing cells. The balance between the activities of these two cell types is controlled by tight transcriptional regulation of both osteoclast-specific and osteoblast-specific genes along with signaling mechanisms that couple the actions of these cells. Defects in the transcriptional control of osteoclasts can result in a failure of either cell differentiation or function. The resulting loss of bone resorption results in the development of osteopetrosis, a condition characterized by dense brittle bones and the lack of a marrow cavity. The use of transgenic gene knock-out mice has elucidated the role of several transcription factors in regulating osteoclast differentiation and function. Null mutations in PU.1 (1), c-Fos (2), and NF-B p50/p52 (3-5) all result in osteopetrosis, thereby indicating that these transcription factors play a critical role in regulating osteoclast biology.Microphthalmia transcription factor (MITF) 2 has been shown to be a regulator of osteoclast function by activ...

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Regulation of the Murine TRACP Gene Promoter

Cited by 15 publications

References 10 publications

Malignant melanoma: genetics and therapeutics in the genomic era

Malignant melanoma: genetics and therapeutics in the genomic era

Microphthalmia transcription factor regulates the expression of the novel osteoclast factor GPNMB

The Expression of Clcn7 and Ostm1 in Osteoclasts Is Coregulated by Microphthalmia Transcription Factor

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