NAIP interacts with hippocalcin and protects neurons against calcium-induced cell death through caspase-3-dependent and -independent pathways

Mercer, Eric A.; Korhonen, Laura; Skoglösa, Ylva; Olsson, Per-Anders; Kukkonen, Jyrki P.; Lindholm, Dan

doi:10.1093/emboj/19.14.3597

Cited by 118 publications

(80 citation statements)

References 52 publications

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“…18 At least 2 other members of the neuronal calcium sensor family promote cell survival: neuronal calcium sensor-1 increases neuronal resistance to several stress factors, 19 and the neuron-restricted visinin-like protein hippocalcin binds neuronal apoptosis-inhibitory protein in an interaction promoted by calcium that facilitates neuronal survival against calcium-induced death stimuli. 20 In this study we show that VSNL1 protects adrenocortical carcinoma cells against calcium-induced apoptosis and promotes survival of these cells that express KCNJ5 G151R , an effect that is ablated in the presence of the calcium channel blocker nifedipine. This leads to the hypothesis that APAs with KCNJ5 mutations may harness the calcium influx to drive cellular proliferation while avoiding calcium-dependent cell death through a mechanism mediated at least in part by VSNL1.…”

Section: Discussionmentioning

confidence: 58%

Visinin-Like 1 Is Upregulated in Aldosterone-Producing Adenomas With KCNJ5 Mutations and Protects From Calcium-Induced Apoptosis

et al. 2012

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Abstract-Visinin-like 1 (VSNL1) is upregulated in aldosterone-producing adenomas (APAs) compared with normal adrenals. We demonstrate that VSNL1 overexpression in adrenocortical carcinoma cells (NCI H295R) upregulates basal and angiotensin II-stimulated CYP11B2 gene expression 3.2-and 1.5-fold, respectively. Conversely, silencing VSNL1 by RNA interference decreases angiotensin II-stimulated CYP11B2 expression and aldosterone secretion by 41.0% and 34.5%, respectively. Mutations in the potassium channel KCNJ5 have been identified in APAs that result in sodium influx and membrane depolarization and are postulated to result in calcium influx in adrenal glomerulosa cells. VSNL1 and CYP11B2 are 8.1-and 6.0-fold more highly expressed, respectively, in APAs harboring KCNJ5 mutations compared with those without, and the upregulation of VSNL1 in these APAs accounts for the overexpression of VSNL1 in the total APA sample set compared with normal adrenals. Silencing VSNL1 in H295R cells renders them sensitive to ionomycin-induced apoptosis, indicating that VSNL1 protects these cells against calcium-induced cell death. Concomitant expression of mutated KCNJ5 (G151R) and silencing VSNL1 results in apoptosis of H295R cells, an effect that is blocked by nifedipine and is absent using a control small-interfering RNA or when wild-type KCNJ5 is expressed and VSNL1 is silenced. These data demonstrate that VSNL1 plays a dual function in vitro in the regulation of CYP11B2 gene expression and in the inhibition of calcium-induced apoptosis. In addition, VSNL1 may play a role in the pathophysiology of APAs harboring mutations in the potassium channel KCNJ5 via its antiapoptotic function in response to calcium cytotoxicity and its effect on aldosterone production. (Hypertension. 2012;59:833-839.)Key Words: VSNL1 Ⅲ KCNJ5 Ⅲ aldosterone-producing adenoma Ⅲ primary aldosteronism Ⅲ aldosterone P rimary aldosteronism (PA) is the most frequent form of endocrine hypertension and is characterized by the excessive production of the mineralocorticoid hormone aldosterone by the adrenal glands.1 A common underlying cause of PA is the presence of an aldosterone-producing adenoma (APA), a benign tumor, also known as Conn syndrome, that is found in 30% to 40% of PA patients. Unilateral adrenalectomy often normalizes or markedly improves the blood pressure in PA patients, and, therefore, APA is the most common, specifically treatable, and potentially curable form of hypertension.

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Section: Discussionmentioning

confidence: 58%

Visinin-Like 1 Is Upregulated in Aldosterone-Producing Adenomas With KCNJ5 Mutations and Protects From Calcium-Induced Apoptosis

et al. 2012

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“…This finding suggests some hitherto unknown functions for this gene in adult hypothalamus and may lead to insights into the pathology of Joubert Syndrome. Similarly, hippocalcin-like 1 (Hpcal1) displays high homology to hippocalcin, a neuron-specific calciumbinding protein highly expressed in hippocampal pyramidal cells, which interacts with neuronal apoptosis inhibitory protein to promote neuronal survival (Mercer et al, 2000). Its marked increase in expression in the developing hypothalamus suggests that Hpcal1 may promote neuronal survival in this region.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Profiling of the Developing Rat Brain Reveals That the Most Dramatic Regional Differentiation in Gene Expression Occurs Postpartum

Stead¹,

Neal²,

Meng³

et al. 2006

J. Neurosci.

106

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Neural development involves the expression of ensembles of regulatory genes that control the coordinate and region-specific expression of a host of other genes, resulting in the unique structure, connectivity, and function of each brain region. Although the role of some specific genes in neural development has been studied in detail, we have no global view of the orchestration of spatial and temporal aspects of gene expression across multiple regions of the developing brain. To this end, we used transcriptional profiling to examine expression levels of 9955 genes in the hypothalamus, hippocampus, and frontal cortex across seven stages of postnatal development and up to four stages of prenatal development in individual male rats (six per group). The results reveal dramatic changes across development in Ͼ97% of the neurally expressed genes. They also uncover a surprising degree of regional differentiation occurring after birth and through the first 2 weeks of life. Cluster analysis identifies 20 clusters of transcripts enriched in genes related to particular functions, such as DNA metabolism, nuclear function, synaptic vesicle transport, myelination, and neuropeptide hormone activity. Thus, groups of genes with related functions change in the brain at specific times, possibly marking critical periods for each function. These findings can broadly serve as a backdrop for studying the role of individual genes in neural development. They also underscore the importance of early postnatal life in the rat, which corresponds to late gestation in the human, as a critical late phase of neural organization and differentiation, even in subcortical regions.

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“…It is well known that hippocalcin protein, along with neuronal apoptosis-inhibitory protein, protects neurons against calcium-induced death stimuli. 22 The second segment of Table 4 shows the top-10 genes with the most significant imprinting effect. One of them is SNP rs3024391 (P ¼ 1.26 Â 10 À5 ), which lies in the intron region of a housekeeping gene called F13A1 on chromosome 6.…”

Section: Application To Fhs Datamentioning

confidence: 99%

Joint detection of association, imprinting and maternal effects using all children and their parents

Han

Lin

2013

Eur J Hum Genet

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Genomic imprinting and maternal effects have been increasingly explored for their contributions to complex diseases. Statistical methods have been proposed to detect both imprinting and maternal effects simultaneously based on nuclear families. However, these methods only make use of case-parents triads and possibly control-parents triads, thus wasting valuable information contained in the siblings. More seriously, most existing methods are full-likelihood based and have to make strong assumptions concerning mating-type probabilities (nuisance parameters) to avoid over-parametrization. In this paper, we develop a partial Likelihood approach for detecting Imprinting and Maternal Effects (LIME), using nuclear families with an arbitrary number of affected and unaffected children. By matching affected children with unaffected ones (within or across families) having the same triad/pair familial genotype combination, we derive a partial likelihood that is free of nuisance parameters. This alleviates the need to make strong, yet unrealistic assumptions about the population, leading to a procedure that is robust to departure from Hardy-Weinberg equilibrium. Power gain by including siblings and robustness of LIME under a variety of settings are demonstrated. Our simulation study also indicates that it is more profitable to recruit additional siblings than additional families when the total number of individuals is kept the same. We applied LIME to the Framingham Heart Study data to demonstrate its utility in analyzing real data. Many of our findings are consistent with results in the literature; potentially novel genes for hypertension have also emerged.

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NAIP interacts with hippocalcin and protects neurons against calcium-induced cell death through caspase-3-dependent and -independent pathways

Cited by 118 publications

References 52 publications

Visinin-Like 1 Is Upregulated in Aldosterone-Producing Adenomas With KCNJ5 Mutations and Protects From Calcium-Induced Apoptosis

Visinin-Like 1 Is Upregulated in Aldosterone-Producing Adenomas With KCNJ5 Mutations and Protects From Calcium-Induced Apoptosis

Transcriptional Profiling of the Developing Rat Brain Reveals That the Most Dramatic Regional Differentiation in Gene Expression Occurs Postpartum

Joint detection of association, imprinting and maternal effects using all children and their parents

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