The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

Farrall, Alexandra L.; Whitelaw, Murray L.

doi:10.1038/onc.2009.228

Cited by 42 publications

(37 citation statements)

References 47 publications

(91 reference statements)

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“…However, to avoid repetition, it suffices to state here that this downregulation of autophagic capacity was related to human carcinogenesis [49,64], and that both high and low LC3 expressing glioblastomas were associated with an improved clinical course depending on patients' Karnofsky Performance Scale score [65]. In this study, as indeed in others [66], the LC3A reaction was high under conditions of hypoxic stress (high HIF1a and LDH5) and low in a microenvironment of increased VD, which suggests induction of autophagy by tumor hypoxia, and suppression of this process in the presence of an adequate nutrient supply; a trend that was clearly seen in the case of beclin 1 [33]. Similarly, low expression of LC3A was associated with melanoma ulceration, but neither low nor high cytoplasmic LC3A reactivity could be clearly associated with the clinical outcome.…”

Section: Discussionmentioning

confidence: 91%

Beclin-1 and LC3A expression in cutaneous malignant melanomas

Sivridis¹,

Koukourakis²,

Mendrinos

et al. 2011

Melanoma Research

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Autophagy is an intracellular pathway for the degradation of long-lived proteins and damaged organelles. It is, in essence, a recycling process allowing cells to survive oxygen and nutrient depletion. The expression of two autophagy-related proteins, beclin 1 and light chain 3A (LC3A) was investigated in 79 nodular cutaneous melanomas. The results were correlated with histopathological factors, vascular density, and hypoxia-related proteins [hypoxia-inducible factors (HIF1α and HIF2α) and lactate dehydrogenase 5]. The reactivity of both autophagy-related proteins was uniformly cytoplasmically diffused. High beclin 1 and LC3A reactivity was related to tumor hypoxia, as this was inferred from the intense expression of HIF1α and lactate dehydrogenase 5, whereas low beclin 1 and LC3A expression was linked with an increased vascular density. In addition, beclin 1 was related to disease-specific survival which, however, exposed a biphasic pattern. A strong beclin 1 expression extending over a tumor area of more than 50% (high) was associated with an increased rate of early deaths, whereas a similarly strong, but less-extensive cytoplasmic reactivity (<10% tumor area; low) defined a sharp fall in the survival 5 years after surgery. Furthermore, the low beclin 1 expression was associated with high Breslow's depth, high Clark's level, and ulceration. Low LC3A expression was also related to ulceration, but not to other histopathological features nor prognosis. In multivariate analysis, beclin 1 was an independent prognostic variable. It is concluded that extensive autophagic activity is generated by tumor hypoxia and anaerobic glycolysis, whereas angiogenesis maintains low autophagic activity. Atg6/beclin 1 was proved to be capable of deciphering the prognosis in cutaneous malignant melanoma, but the matter requires further investigation.

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Section: Discussionmentioning

confidence: 91%

Beclin-1 and LC3A expression in cutaneous malignant melanomas

Sivridis¹,

Koukourakis²,

Mendrinos

et al. 2011

Melanoma Research

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“…As with other bHLH/PAS proteins (28,29), there is evidence that the C terminus functions primarily as a transactivation or transrepression domain. By analogy, the closely related bHLH/PAS transcription factor SIM2 is known to regulate transcription differentially in a context-dependent manner (30,31). SIM1 has variously been shown to activate and repress transcription in cell-based reporter assays.…”

Section: Figurementioning

confidence: 99%

Rare variants in single-minded 1 (SIM1) are associated with severe obesity

Ramachandrappa¹,

Raimondo²,

Cali³

et al. 2013

J. Clin. Invest.

144

113

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Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. Obesity has been reported in Sim1 haploinsufficient mice and in a patient with a balanced translocation disrupting SIM1. We sequenced the coding region of SIM1 in 2,100 patients with severe, early onset obesity and in 1,680 controls. Thirteen different heterozygous variants in SIM1 were identified in 28 unrelated severely obese patients. Nine of the 13 variants significantly reduced the ability of SIM1 to activate a SIM1-responsive reporter gene when studied in stably transfected cells coexpressing the heterodimeric partners of SIM1 (ARNT or ARNT2). SIM1 variants with reduced activity cosegregated with obesity in extended family studies with variable penetrance. We studied the phenotype of patients carrying variants that exhibited reduced activity in vitro. Variant carriers exhibited increased ad libitum food intake at a test meal, normal basal metabolic rate, and evidence of autonomic dysfunction. Eleven of the 13 probands had evidence of a neurobehavioral phenotype. The phenotypic similarities between patients with SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling.

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“…Hepa-1c1c7 cells were seeded on 75-cm 2 tissue culture flasks and grown to confluence. Cells were treated with vehicle alone (0.1% DMSO) or 10 M YH439 or grown in suspension cultures for 5 h. Hypoxic cells (1% O 2 ) were also prepared by transferring cells to a Ruskinn Invivo 2 400 hypoxia chamber and incubated for 4 h. Chromatin immunoprecipitation (ChIP) was performed with antibodies against either AhR (RPT9; Abcam), hypoxia-inducible factor (HIF)-1␣ (Abcam), Myc epitope tag (Abcam), or nonspecific control IgG (Millipore/Jackson ImmunoResearch Laboratories, West Grove, PA) as described previously (Farrall and Whitelaw, 2009). Fold enrichment was calculated using the 2…”

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confidence: 99%

Xenobiotics and Loss of Cell Adhesion Drive Distinct Transcriptional Outcomes by Aryl Hydrocarbon Receptor Signaling

et al. 2012

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The aryl hydrocarbon receptor (AhR) is a signal-regulated transcription factor, which is canonically activated by the direct binding of xenobiotics. In addition, switching cells from adherent to suspension culture also activates the AhR, representing a nonxenobiotic, physiological activation of AhR signaling. Here, we show that the AhR is recruited to target gene enhancers in both ligand [isopropyl-2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2-yl)carbamoyl]acetate (YH439)]-treated and suspension cells, suggesting a common mechanism of target gene induction between these two routes of AhR activation. However, gene expression profiles critically differ between xenobiotic-and suspension-activated AhR signaling. Por and Cldnd1 were regulated predominantly by ligand treatments, whereas, in contrast, ApoER2 and Ganc were regulated predominantly by the suspension condition. Classic xenobioticmetabolizing AhR targets such as Cyp1a1, Cyp1b1, and Nqo1 were regulated by both ligand and suspension conditions. Temporal expression patterns of AhR target genes were also found to vary, with examples of transient activation, transient repression, or sustained alterations in expression. Furthermore, sequence analysis coupled with chromatin immunoprecipitation assays and reporter gene analysis identified a functional xenobiotic response element (XRE) in the intron 1 of the mouse Tiparp gene, which was also bound by hypoxia-inducible factor-1␣ during hypoxia and features a concatemer of four XRE cores (GCGTG). Our data suggest that this XRE concatemer site concurrently regulates the expression of both the Tiparp gene and its cis antisense noncoding RNA after ligand-or suspension-induced AhR activation. This work provides novel insights into how AhR signaling drives different transcriptional programs via the ligand versus suspension modes of activation.

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The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

Cited by 42 publications

References 47 publications

Beclin-1 and LC3A expression in cutaneous malignant melanomas

Beclin-1 and LC3A expression in cutaneous malignant melanomas

Rare variants in single-minded 1 (SIM1) are associated with severe obesity

Xenobiotics and Loss of Cell Adhesion Drive Distinct Transcriptional Outcomes by Aryl Hydrocarbon Receptor Signaling

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