ASPP1 and ASPP2 bind active RAS, potentiate RAS signalling and enhance p53 activity in cancer cells

Wang, Yong; Godin-Heymann, Nadia; Wang, X Dan; Bergamaschi, Daniele; Llanos, Susana; Lü, Xin

doi:10.1038/cdd.2013.3

Cited by 57 publications

(74 citation statements)

References 38 publications

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“…The identification of ASPP2 as a novel transcriptional target of STAT1 and the finding that LPS and IFNs can induce ASPP2 expression suggest that it may also act as a sensor of infection. ASPP2 may also promote phosphorylation of STAT1 through the potentiating RAS-MAPK pathway (37), which forms an autoregulation loop (Fig. 5D).…”

Section: Discussionmentioning

confidence: 99%

“…In polarized epithelial cells, including CP epithelial cells, ASPP2 is located at TJs (21). On RAS activation, ASPP2 is translocated to the cytoplasm and enhances the apoptotic function of p53 (37). The ability of ASPP2 to stimulate the apoptotic function of p53 and p73 is mediated by its C terminus, which is localized in the nucleus (19).…”

Section: Discussionmentioning

confidence: 99%

“…The function of ASPP2 as a gatekeeper could be caused by its ability to regulate cell polarity and RAS signaling through its N terminus (37). In polarized epithelial cells, including CP epithelial cells, ASPP2 is located at TJs (21).…”

Section: Discussionmentioning

confidence: 99%

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STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression

Turnquist¹,

Wang²,

Severson³

et al. 2014

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

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Significance Two of the most debilitating and scientifically challenging diseases of the 21st century are cancer and neurodegeneration. Although cancer results from excessive cell growth, neurodegeneration is a consequence of excessive cell loss. Dysfunction of the same key regulators, including oncogenes and tumor suppressors, may cause both diseases. We report that LPS and IFN induce apoptosis-stimulating protein of p53 with signature sequences of ankyrin repeat-, SH3 domain-, and proline-rich region-containing protein 2 (ASPP2) transcription through a signal transducer and activator of transcription 1 (STAT1) -dependent but NF-κB RELA/p65-independent pathway and that ASPP2 mediates LPS-induced apoptosis. Thus, the identified STAT1/ASPP2 pathway reveals an important function of ASPP2 in the cellular response to inflammation and infection and connects neuroinflammation to cell polarity and tumor suppression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression

Turnquist¹,

Wang²,

Severson³

et al. 2014

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

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“…ASPP2 mediates oncogenic RASinduced senescence by preventing oncogenic RAS from inducing autophagy (27), and SUMO-modification and nuclear induction of Cyclin D1 (26), both required for RAS' full oncogenic function. ASPP2 can also enhance oncogenic RAS-induced apoptosis in cancer cells (37). Hence, loss of ASPP2 potentiates the tumorigenic properties of oncogenic RAS.…”

Section: Discussionmentioning

confidence: 99%

ASPP2 suppresses squamous cell carcinoma via RelA/p65–mediated repression of p63

Tordella¹,

Koch²,

Salter³

et al. 2013

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

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Squamous cell carcinoma (SCC) is highly malignant and refractory to therapy. The majority of existing mouse SCC models involve multiple gene mutations. Very few mouse models of spontaneous SCC have been generated by a single gene deletion. Here we report a haploinsufficient SCC mouse model in which exon 3 of the Tp53BP2 gene (a p53 binding protein) was deleted in one allele in a BALB/c genetic background. Tp53BP2 encodes ASPP2 (ankyrin repeats, SH3 domain and protein rich region containing protein 2). Keratinocyte differentiation induces ASPP2 and its expression is inversely correlated with p63 protein in vitro and in vivo. Upregulation of p63 expression is required for ASPP2 Δexon3/+ BALB/c mice to develop SCC, as heterozygosity of p63 but not p53 prevents them from developing it. Mechanistically, ASPP2 inhibits ΔNp63 expression through its ability to bind IκB and enhance nuclear Rel/A p65, a component of the NF-κB transcription complex, which mediates the repression of p63. Reduced ASPP2 expression associates with tumor metastasis and increased p63 expression in human head and neck SCCs. This study identifies ASPP2 as a tumor suppressor that suppresses SCC via inflammatory signaling through NF-κB-mediated repression of p63.inflammation | T53BP2 | stratified epithelial cell tumor

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“…EGFR can reduce ASPP2-induced apoptosis by the activation of the PI3K/Akt signaling pathway in hepatoma cells [14]. In colorectal cancer cells, ASPP2 induces apoptosis by binding and activating the RAS/PI3K/AKT signaling pathway [15, 16]. Therefore, the PI3K/Akt signaling pathway plays a critical role in tumor cell apoptosis and the discovery of lung cancer targeted drugs.…”

Section: Introductionmentioning

confidence: 99%

Effect of miR-21 on Apoptosis in Lung Cancer Cell Through Inhibiting the PI3K/ Akt/NF-κB Signaling Pathway in Vitro and in Vivo

Zhou

Wang

Sun

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lung cancer is one of the most common malignancies in the world. Apoptosis-stimulating protein of p53 (ASPP2), a tumorigenesis related protein, plays a critical role in the initiation and development of various types of cancers. However, the effect of ASPP2 on lung cancer remains unknown. The purpose of this study aims to investigate the mechanism of ASPP2 regulated by miR-21 in lung cancer in vitro and in vivo. Methods: In the study, migration and invasion assays, apoptosis assay, caspase activity assay, TUNEL staining, real time PCR and western blot were used to investigate the mechanism of ASPP2 regulated by miR-21 in lung cancer in vitro and in vivo. Results: We demonstrated that the miR-21 inhibitor induced apoptosis through inhibiting the PI3K/Akt/NF-κB signaling pathway in non-small cell lung carcinoma (NSCLC). Moreover, ASPP2 was directly targeted by miR-21 in NSCLC cells. Down-regulation of miR-21 suppressed cell migration and invasion, as well as the EMT signaling pathway in NSCLC cells. Furthermore, the miR-21 inhibitor induced cell apoptosis via the caspase dependent pathway in NSCLC cells. The miR-21 inhibitor enhanced caspase-3, 8, 9 activity in NSCLC cells. In addition, the caspase inhibitor significantly reduced the apoptosis induced by the miR-21 inhibitor in NSCLC cells. Conclusions: Our results revealed that the miR-21 inhibitor could induce apoptosis through inhibiting the PI3K/Akt/NF-κB signaling pathway in human NSCLC cells, and might serve as a therapeutic strategy to treat NSCLC.

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ASPP1 and ASPP2 bind active RAS, potentiate RAS signalling and enhance p53 activity in cancer cells

Cited by 57 publications

References 38 publications

STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression

STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression

ASPP2 suppresses squamous cell carcinoma via RelA/p65–mediated repression of p63

Effect of miR-21 on Apoptosis in Lung Cancer Cell Through Inhibiting the PI3K/ Akt/NF-κB Signaling Pathway in Vitro and in Vivo

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