ABCC6 Expression Is Regulated by CCAAT/Enhancer-Binding Protein Activating a Primate-Specific Sequence Located in the First Intron of the Gene

Ratajewski, Marcin; Boussac, Hugues de; Sachrajda, Iwona; Bacquet, Caroline; Kovàcs, Tündé; Váradi, András; Pułaski, Łukasz; Arányi, Tamàs

doi:10.1038/jid.2012.218

Cited by 16 publications

(30 citation statements)

References 51 publications

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“…It was further demonstrated that hepatocyte nuclear factor 4a (HNF4a) and CCAAT/enhancer binder protein b (C/EBPb) bind to the proximal promoter and the primate-specific second intronic HS. These results suggested that C/EBPb forms a complex with other regulatory proteins, including previously identified regulatory factor HNF4a (De Boussac et al, 2010;Ratajewski et al, 2012). These data attest to the complex tissue-and primate-specific expression of the ABCC6 gene, a topic that was also addressed by the keynote speaker, Dr László Nagy, University of Debrecen, Hungary.…”

Section: Toward Treatmentmentioning

confidence: 62%

Pseudoxanthoma Elasticum: Progress in Research Toward Treatment: Summary of the 2012 PXE International Research Meeting

Uitto

Váradi

Bercovitch

et al. 2013

Journal of Investigative Dermatology

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Section: Toward Treatmentmentioning

confidence: 62%

Pseudoxanthoma Elasticum: Progress in Research Toward Treatment: Summary of the 2012 PXE International Research Meeting

Uitto

Váradi

Bercovitch

et al. 2013

Journal of Investigative Dermatology

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“…There is also intestinal expression of the gene based on the data published by (Kool et al, 1999) and findings in human cell lines (Ratajewski et al, 2012). This expression pattern is similar in rodents and human even if the gene is in a dynamically evolving genomic region (Eichler et al, 2007; Symmons et al, 2008).…”

Section: Transcriptional Regulation Of the Abcc6 Genementioning

confidence: 99%

Transcriptional regulation of the ABCC6 gene and the background of impaired function of missense disease-causing mutations

Arányi¹,

Bacquet²,

Boussac³

et al. 2013

Front. Genet.

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The human ATP-binding cassette family C member 6 (ABCC6) gene encodes an ABC transporter protein expressed primarily in the liver and to a lesser extent in the kidneys and the intestines. We review here the mechanisms of this restricted tissue-specific expression and the role of hepatocyte nuclear factor 4α which is responsible for the expression pattern. Detailed analyses uncovered further regulators of the expression of the gene pointing to an intronic primate-specific regulator region, an activator of the expression of the gene by binding CCAAT/enhancer-binding protein beta, which interacts with other proteins acting in the proximal promoter. This regulatory network is affected by various environmental stimuli including oxidative stress and the extracellular signal-regulated protein kinases 1 and 2 pathway. We also review here the structural and functional consequences of disease-causing missense mutations of ABCC6. A significant clustering of the missense disease-causing mutations was found at the domain–domain interfaces. This clustering means that the domain contacts are much less permissive to amino acid replacements than the rest of the protein. We summarize the experimental methods resulting in the identification of mutants with preserved transport activity but failure in intracellular targeting. These mutants are candidates for functional rescue by chemical chaperons. The results of such research can provide the basis of future allele-specific therapy of ABCC6-mediated disorders like pseudoxanthoma elasticum or the generalized arterial calcification in infancy.

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“…Hbb th3/+ mice did not develop spontaneous calcification as seen in Abcc 6 −/− mice probably because the ABCC6 protein decrease occurred late in life and/or was insufficient to promote mineralization in the Hbb th3/+ mouse with the DCC-resistant C57BL/6J genetic background (Martin et al, 2011). Nevertheless, as the transcriptional regulation of the mouse and human ABCC 6 genes is similar (Aranyi et al, 2005; Douet et al, 2006, 2007; de Boussac et al, 2010; Ratajewski et al, 2012), it is likely that the human β-thalassemia phenotype could induce comparable molecular changes leading to a suboptimal endowment in ABCC6 and increased susceptibility to ectopic mineralization in a PXE-like manner.…”

Section: The Pathophysiologies Associated With Abcc6 Deficiencymentioning

confidence: 99%

The molecular and physiological roles of ABCC6: more than meets the eye

Saux¹,

Martin²,

Aherrahrou³

et al. 2012

Front. Gene.

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Abnormal mineralization occurs in the context of several common conditions, including advanced age, diabetes, hypercholesterolemia, chronic renal failure, and certain genetic conditions. Metabolic, mechanical, infectious, and inflammatory injuries promote ectopic mineralization through overlapping yet distinct molecular mechanisms of initiation and progression. The ABCC6 protein is an ATP-dependent transporter primarily found in the plasma membrane of hepatocytes. ABCC6 exports unknown substrates from the liver presumably for systemic circulation. ABCC6 deficiency is the primary cause for chronic and acute forms of ectopic mineralization described in diseases such as pseudoxanthoma elasticum (PXE), β-thalassemia, and generalized arterial calcification of infancy (GACI) in humans and dystrophic cardiac calcification (DCC) in mice. These pathologies are characterized by mineralization of cardiovascular, ocular, and dermal tissues. PXE and to an extent GACI are caused by inactivating ABCC6 mutations, whereas the mineralization associated with β-thalassemia patients derives from a liver-specific change in ABCC6 expression. DCC is an acquired phenotype resulting from cardiovascular insults (ischemic injury or hyperlipidemia) and secondary to ABCC6 insufficiency. Abcc6-deficient mice develop ectopic calcifications similar to both the human PXE and mouse DCC phenotypes. The precise molecular and cellular mechanism linking deficient hepatic ABCC6 function to distal ectopic mineral deposition is not understood and has captured the attention of many research groups. Our previously published work along with that of others show that ABCC6 influences other modulators of calcification and that it plays a much greater physiological role than originally thought.

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ABCC6 Expression Is Regulated by CCAAT/Enhancer-Binding Protein Activating a Primate-Specific Sequence Located in the First Intron of the Gene

Cited by 16 publications

References 51 publications

Pseudoxanthoma Elasticum: Progress in Research Toward Treatment: Summary of the 2012 PXE International Research Meeting

Pseudoxanthoma Elasticum: Progress in Research Toward Treatment: Summary of the 2012 PXE International Research Meeting

Transcriptional regulation of the ABCC6 gene and the background of impaired function of missense disease-causing mutations

The molecular and physiological roles of ABCC6: more than meets the eye

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