The Down-regulation of the Human MYC Gene by the Nuclear Hormone 1α,25-dihydroxyvitamin D3 is Associated with Cycling of Corepressors and Histone Deacetylases

Toropainen, Sari; Vaïsänen, Sami; Heikkinen, Sami; Carlberg, Carsten

doi:10.1016/j.jmb.2010.05.031

Cited by 71 publications

(54 citation statements)

References 39 publications

(34 reference statements)

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“…We also observed a gradual diminution of MYC mRNA over 24 h (Fig. 1C), in agreement with other studies (35,36). In contrast, there was an almost total loss of c-MYC protein over the same period, whereas expression of c-MYC heterodimeric partner MAX was unaffected ( Importantly, coimmunoprecipitation studies showed that 1,25D treatment induced a rapid association (<4 h) of the VDR with c-MYC, suggesting that 1,25D may control c-MYC stability (Fig.…”

Section: Resultssupporting

confidence: 93%

“…c-MYC and FoxO proteins are often regulated by common mechanisms with opposing effects. For example, both are ubiquitinated by p45 SKP2 (33, 34), which induces FoxO protein turnover, but coactivates c-MYC.Recent studies have shown that 1,25D gradually reduces MYC RNA levels in cancer cells (35,36). Because signaling through the VDR enhances FoxO protein function (19), we investigated potential mechanisms of cross-talk between c-MYC and VDR signaling.…”

mentioning

confidence: 99%

“…Recent studies have shown that 1,25D gradually reduces MYC RNA levels in cancer cells (35,36). Because signaling through the VDR enhances FoxO protein function (19), we investigated potential mechanisms of cross-talk between c-MYC and VDR signaling.…”

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confidence: 99%

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Vitamin D receptor as a master regulator of the c-MYC/MXD1 network

Salehi-Tabar¹,

Nguyen-Yamamoto²,

Tavera-Mendoza³

et al. 2012

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

111

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Vitamin D signaling regulates cell proliferation and differentiation, and epidemiological data suggest that it functions as a cancer chemopreventive agent, although the underlying mechanisms are poorly understood. Vitamin D signaling can suppress expression of genes regulated by c-MYC, a transcription factor that controls epidermal differentiation and cell proliferation and whose activity is frequently elevated in cancer. We show through cell-and animal-based studies and mathematical modeling that hormonal 1,25-dihydroxyvitamin D (1,25D) and the vitamin D receptor (VDR) profoundly alter, through multiple mechanisms, the balance in function of c-MYC and its antagonist the transcriptional repressor MAD1/MXD1. 1,25D inhibited transcription of c-MYC-regulated genes in vitro, and topical 1,25D suppressed expression of c-MYC and its target setd8 in mouse skin, whereas MXD1 levels increased. 1,25D inhibited MYC gene expression and accelerated its protein turnover. In contrast, it enhanced MXD1 expression and stability, dramatically altering ratios of DNA-bound c-MYC and MXD1. Remarkably, F-box protein FBW7, an E3-ubiquitin ligase, controlled stability of both arms of the c-MYC/MXD1 push-pull network, and FBW7 ablation attenuated 1,25D regulation of c-MYC and MXD1 turnover. Additionally, c-MYC expression increased upon VDR knockdown, an effect abrogated by ablation of MYC regulator β-catenin. c-MYC levels were widely elevated in vdr −/− mice, including in intestinal epithelium, where hyperproliferation has been reported, and in skin epithelia, where phenotypes of VDR-deficient mice and those overexpressing epidermal c-MYC are similar. Thus, 1,25D and the VDR regulate the c-MYC/MXD1 network to suppress c-MYC function, providing a molecular basis for cancer preventive actions of vitamin D.V itamin D is obtained naturally from limited dietary sources. It is also generated by cutaneous conversion of 7-dehydrocholesterol in the presence of adequate surface solar UV-B radiation, which varies with latitude and time of year (1). Vitamin D has attracted broad clinical interest because insufficiency or deficiency is widespread in several populations worldwide (2-4). Although initially identified as a regulator of calcium homeostasis, vitamin D is now known to have a broad spectrum of actions, driven by the virtually ubiquitous expression of the vitamin D receptor (VDR), a nuclear receptor and hormone-regulated transcription factor. For example, it acts as a chemopreventive agent in several animal models of cancer and induces cell-cycle arrest and nonmalignant and malignant cell differentiation (5-11). Epidemiological data have provided associations between lack of UV-B exposure, vitamin D insufficiency, and the prevalence of certain cancers (12). A large prospective study associated vitamin D sufficiency with reduced total cancer incidence and mortality, particularly in digestive cancers [head and neck squamous cell carcinoma (HNSCC), esophageal, pancreatic, stomach, and colorectal cancers] and leukemias (13). VDR gene polymorphi...

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Section: Resultssupporting

confidence: 93%

mentioning

confidence: 99%

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Vitamin D receptor as a master regulator of the c-MYC/MXD1 network

Salehi-Tabar¹,

Nguyen-Yamamoto²,

Tavera-Mendoza³

et al. 2012

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

111

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“…Salmon et al 24 have previously characterized a KLF4-centered repressor complex with HDAC2 being a core component responsible for SM22α repression during SMC PM. Because HDACs mostly function in large complexes and HDAC11 has been shown to be corecruited with HDAC2 to gene promoters in at least 1 instance, 25 it is not unconceivable that HDAC11 could be steered to the SMC signature gene promoters as part of a corepressor complex by KLF4 to directly repress transcription. In the same vein, it is worthwhile to pursue a genome-wide binding pattern for HDAC11 under both physiological and pathological circumstances in SMCs.…”

Section: Discussionmentioning

confidence: 99%

Angiogenic Factor With G Patch and FHA Domains 1 Is a Novel Regulator of Vascular Injury

Zhou

Zeng

et al. 2017

ATVB

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Objective— Phenotypic modulation of vascular smooth muscle cells represents a hallmark event in vascular injury. The underlying mechanism is not completely sorted out. We investigated the involvement of angiogenic factor with G patch and FHA domains 1 (Aggf1) in vascular injury focusing on the transcriptional regulation of vascular smooth muscle cell signature genes. Approach and Results— We report here that Aggf1 expression was downregulated in several different cell models of phenotypic modulation in vitro and in the vessels after carotid artery ligation in mice. Adenovirus-mediated Aggf1 overexpression dampened vascular injury and normalized vascular smooth muscle cell signature gene expression. Mechanistically, Aggf1 interacted with myocardin and was imperative for the formation of a serum response factor–myocardin complex on gene promoters. In response to injurious stimuli, kruppel-like factor 4 was recruited to the Aggf1 promoter and enlisted histone deacetylase 11 to repress Aggf1 transcription. In accordance, depletion of kruppel-like factor 4 or histone deacetylase 11 restored Aggf1 expression and abrogated vascular smooth muscle cell phenotypic modulation. Finally, treatment of a histone deacetylase 11 inhibitor attenuated vascular injury in mice. Conclusions— Therefore, we have unveiled a previously unrecognized role for Aggf1 in regulating vascular injury.

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“…Thus, unliganded or antagonist-bound VDR recruits NCoR/SMRT corepressor complexes containing HDACs leading to a compaction of chromatin near the transcriptional promoter. Gene activation involves the 1,25(OH) 2 D 3 -induced release of NCoR/SMRT-mediated repression and subsequent ubiquitinylation and degradation of corepressors presumably mediated through the transducer beta-like 1, X-linked (TBL1X) exchange factor [133,134].…”

Section: Smrt and Ncormentioning

confidence: 99%