Amyloid-β precursor-like protein APLP1 is a novel p53 transcriptional target gene that augments neuroblastoma cell death upon genotoxic stress

Tang, Xiaohu; Milyavsky, Michael; Goldfinger, Naomi; Rotter, Varda

doi:10.1038/sj.onc.1210542

Cited by 30 publications

(33 citation statements)

References 38 publications

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“…CFD , known to be important in immune defense in tissue [48], possibly participates in inflammation of gastric epithelium [49]. APLP1 , a transcriptional target of p53, may be involved in cell death [50] and therefore vorinostat-induced expression of APLP1 may contribute to apoptotic cell death observed in our study. NQO1 inactivation has been associated with increased susceptibility to a variety of carcinogens [51], and has been related to the risk of colorectal cancer [52], [53].…”

Section: Discussionmentioning

confidence: 50%

Gene Expression Signature Analysis Identifies Vorinostat as a Candidate Therapy for Gastric Cancer

et al. 2011

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BackgroundGastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future.Methodology/Principal FindingsUsing microarray technology, we generated a gene expression profile of human gastric cancer–specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A) whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern.Conclusions/SignificanceWe showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment.

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Section: Discussionmentioning

confidence: 50%

Gene Expression Signature Analysis Identifies Vorinostat as a Candidate Therapy for Gastric Cancer

et al. 2011

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“…In another study, the apoptosis triggering mechanism of AICD was shown to involve enhancement of p53-mediated apoptosis [103]. Recently, a study by Tang et al demonstrated that the APLP1 gene is a direct transcriptional target of p53 [104]. It was further shown that knock-down of APLP1 reduced stress-induced apoptosis in neuroblastoma cells, whereas overexpression of APLP1 enhanced it.…”

Section: Neuronal Survival and Apoptosismentioning

confidence: 95%

Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors

Jacobsen

Iverfeldt

2009

Cell. Mol. Life Sci.

111

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The Alzheimer's amyloid precursor protein (APP) belongs to a conserved gene family that also includes the mammalian APLP1 and APLP2, the Drosophila APPL, and the C. elegans APL-1. The biological function of APP is still not fully clear. However, it is known that the APP family proteins have redundant and partly overlapping functions, which demonstrates the importance of studying all APP family members to gain a more complete picture. When APP was first cloned, it was speculated that it could function as a receptor. This theory has been further substantiated by studies showing that APP and its homologues bind both extracellular ligands and intracellular adaptor proteins. The APP family proteins undergo regulated intramembrane proteolysis (RIP), generating secreted and cytoplasmic fragments that have been ascribed different functions. In this review, we will discuss the APP family with focus on biological functions, binding partners, and regulated processing.

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“…S3a). Also examined by qRT-PCR were PAI-1 (plasminogen activator inhibitor-1)22, IGFBP7 (insulin-like growth factor binding protein 7)23, MMP3 (matrix metallo-protease 3)24, BUB1 (budding uninhibited by benzimidazoles 1 homolog)25 and CDC20 (cell division cycle 20 homolog)26, which were reported to be upregulated (the former three) or downregulated (the latter two) at cellular senescence27 and predicted (IGFBP7: www2.ba.itb.cnr.it/p53FamTaG) or experimentally shown (the other four) to be transcriptionally regulated by p5322, 25–27. These genes were found to be changed in expression in the expected directions (Fig.…”

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confidence: 99%

p53 isoforms Δ133p53 and p53β are endogenous regulators of replicative cellular senescence

et al. 2009

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The finite proliferative potential of normal human cells leads to replicative cellular senescence, which is a critical barrier to tumour progression in vivo1–3. We show that human p53 isoforms (Δ133p53 and p53β)4 constitute an endogenous regulatory mechanism for p53-mediated replicative senescence. Induced p53β and diminished Δ133p53 were associated with replicative senescence, but not oncogene-induced senescence, in normal human fibroblasts. The replicatively senescent fibroblasts also expressed increased levels of miR-34a, a p53-induced microRNA5–9, the antisense inhibition of which delayed the onset of replicative senescence. The siRNA-mediated knockdown of endogenous Δ133p53 induced cellular senescence, which was attributed to the regulation of p21WAF1 and other p53 transcriptional target genes. In overexpression experiments, while p53β cooperated with full-length p53 to accelerate cellular senescence, Δ133p53 repressed miR-34a expression and extended cellular replicative lifespan, providing a functional connection of this microRNA to the p53 isoform-mediated regulation of senescence. The senescence-associated signature of p53 isoform expression (i.e., elevated p53β and reduced Δ133p53) was observed in vivo in colon adenomas with senescent phenotypes10, 11. The increased Δ133p53 and decreased p53β isoform expression found in colon carcinoma may signal an escape from the senescence barrier during the progression from adenoma to carcinoma.

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Amyloid-β precursor-like protein APLP1 is a novel p53 transcriptional target gene that augments neuroblastoma cell death upon genotoxic stress

Cited by 30 publications

References 38 publications

Gene Expression Signature Analysis Identifies Vorinostat as a Candidate Therapy for Gastric Cancer

Gene Expression Signature Analysis Identifies Vorinostat as a Candidate Therapy for Gastric Cancer

Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors

p53 isoforms Δ133p53 and p53β are endogenous regulators of replicative cellular senescence

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