SPATA18, a Spermatogenesis-Associated Gene, Is a Novel Transcriptional Target of p53 and p63

Bornstein, Chamutal; Brosh, Ran; Molchadsky, Alina; Madar, Shalom; Kogan-Sakin, Ira; Goldstein, Ido; Chakravarti, Deepavali; Flores, Elsa R.; Goldfinger, Naomi; Sarig, Rachel; Rotter, Varda

doi:10.1128/mcb.01072-10

Cited by 39 publications

(31 citation statements)

References 61 publications

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“…The Rfx family of transcription factors is implicated in regulation of ciliary biogenesis (Chu et al, 2010). We additionally provide evidence that Spata18 , a target gene of both p53 and p63 (Bornstein et al, 2011), is regulated by p73 (Figure 5B and C). …”

Section: Resultsmentioning

confidence: 53%

p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network

et al. 2016

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Summary We report that p73 is expressed in multiciliated cells (MCCs), is required for MCC differentiation, and directly regulates transcriptional modulators of multiciliogenesis. Loss of ciliary biogenesis provides a unifying mechanism for many phenotypes observed in p73 knockout mice including hydrocephalus, hippocampal dysgenesis, sterility and chronic inflammation/infection of lung, middle ear and sinus. Through p73 and p63 ChIP-seq using murine tracheal cells, we identified over 100 putative p73 target genes that regulate MCC differentiation and homeostasis. We validated Foxj1, a transcriptional regulator of multiciliogenesis, and many other cilia-associated genes as direct target genes of p73 and p63. We show p73 and p63 are co-expressed in a subset of basal cells, and suggest that p73 ‘marks’ these cells for MCC differentiation. In sum, p73 is essential for MCC differentiation, functions as a critical regulator of a transcriptome required for MCC differentiation and, like p63, has an essential role in development of tissues.

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Section: Resultsmentioning

confidence: 53%

p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network

et al. 2016

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“…It is known that a TP53-inducible protein, Mieap (also referred to as Spata18) (18), controls mitochondrial quality through interaction with the HIF-1-inducible protein BNIP3 (19). In addition, Mieap has been proposed to induce the accumulation of lysosomal proteins within mitochondria by way of repairing damaged mitochondria (20).…”

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confidence: 99%

Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

Brahimi-Horn

Lacas‐Gervais

Adaixo

et al. 2015

Molecular and Cellular Biology

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The oxygen-limiting (hypoxic) microenvironment of tumors induces metabolic reprogramming and cell survival, but the underlying mechanisms involving mitochondria remain poorly understood. We previously demonstrated that hypoxia-inducible factor 1 mediates the hyperfusion of mitochondria by inducing Bcl-2/adenovirus E1B 19-kDa interacting protein 3 and posttranslational truncation of the mitochondrial ATP transporter outer membrane voltage-dependent anion channel 1 in hypoxic cells. In addition, we showed that truncation is associated with increased resistance to drug-induced apoptosis and is indicative of increased patient chemoresistance. We now show that silencing of the tumor suppressor TP53 decreases truncation and increases drug-induced apoptosis. We also show that TP53 regulates truncation through induction of the mitochondrial protein Mieap. While we found that truncation was independent of mitophagy, we observed local microfusion between mitochondria and endolysosomes in hypoxic cells in culture and in patients' tumor tissues. Since we found that the endolysosomal asparagine endopeptidase was responsible for truncation, we propose that it is a readout of mitochondrial-endolysosomal microfusion in hypoxia. These novel findings provide the framework for a better understanding of hypoxic cell metabolism and cell survival through mitochondrial-endolysosomal microfusion regulated by hypoxia-inducible factor 1 and TP53. Hypoxia is a natural occurring stress that results in compensatory changes in metabolism and cell survival during embryonic development and tumor growth. Hypoxia stabilizes and activates the transcription factor hypoxia-inducible factor (HIF) through inhibition of oxygen-dependent hydroxylases that earmark the alpha subunit of HIF for proteasomal degradation (1). HIF induces or represses the expression of genes implicated in a myriad of functions, including those regulating metabolism and resistance to drug-induced cell death. Genes coding for the enzymes of the glycolytic pathway, including hexokinase, are highly induced by HIF-1, and this is in part responsible for the switch in metabolism from mitochondrial respiration to glycolysis in cancer cells. Considerable studies have pointed to the Warburg effect, also termed aerobic glycolysis, as the major adaptive response of cancer cells, but mitochondrial metabolism and mitochondrial dynamics are also starting to be recognized as important adaptive strategies of cancer cells (2). Mitochondria are critical organelles that regulate both metabolism and cell death. They are dynamic organelles that continuously undergo fission and fusion during cell growth (3, 4). Under stress conditions, such as nutrient depletion or hypoxia, mitochondria either fragment or are degraded by HIF-dependent mitophagy (mitochondrial removal by autophagy) (5) or hyperfuse together to form elongated or rounded structures that optimize ATP production and promote cell survival (6-11).We reported previously that certain cell lines exposed to hypoxia contained enlarged mitochon...

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“…The frequently up‐regulated p53 targets encompass a range of functional types, including cell cycle inhibitors ( CDKN1A ), apoptosis mediators ( TNFRSF10C , AEN , BBC3 ), p53 regulators ( MDM2 ) and DNA damage responders ( DDB2 ). Some are established p53 targets; yet others (eg SPATA18 , EDA2R , PHLDA3 ) have only recently been identified as p53‐induced targets and are not well characterized [, ].…”

Section: Resultsmentioning

confidence: 99%

Effects of TP53 mutational status on gene expression patterns across 10 human cancer types

Parikh

Hilsenbeck

Creighton

et al. 2014

The Journal of Pathology

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Mutations in the TP53 tumor suppressor gene occur in half of all human cancers, indicating its critical importance in inhibiting cancer development. Despite extensive studies, the mechanisms by which mutant p53 enhances tumor progression remain only partially understood. Here, using data from The Cancer Genome Atlas (TCGA), genomic and transcriptomic analyses were performed on 2256 tumors from ten human cancer types. We show that tumors with TP53 mutations have altered gene expression profiles compared to tumors retaining two wildtype TP53 alleles. Among 113 known p53 upregulated target genes identified from cell culture assays, ten were consistently upregulated in at least 8 of 10 cancer types that retain both copies of wildtype TP53. RPS27L, CDKN1A (p21CIP1), and ZMAT3 were significantly upregulated in all ten cancer types retaining wildtype TP53. Using this p53-based expression analysis as a discovery tool, we used cell-based assays to identify five novel p53 target genes from genes consistently upregulated in wildtype p53 cancers. Global gene expression analyses revealed that cell cycle regulatory genes and transcription factors E2F1, MYBL2, and FOXM1 were disproportionately upregulated in many TP53 mutant cancer types. Finally, over 93% of tumors with a TP53 mutation exhibited greatly reduced wildtype p53 messenger expression due to loss of heterozygosity or copy neutral loss of heterozygosity, supporting the concept of p53 as a recessive tumor suppressor. The data indicate that tumors with wildtype TP53 retain some aspects of p53-mediated growth inhibitory signaling through activation of p53 target genes and suppression of cell cycle regulatory genes.

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SPATA18, a Spermatogenesis-Associated Gene, Is a Novel Transcriptional Target of p53 and p63

Cited by 39 publications

References 61 publications

p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network

p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network

Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

Effects of TP53 mutational status on gene expression patterns across 10 human cancer types

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