TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activity

Tomasini, Richard; Seux, Mylène; Nowak, Jonathan A.; Bontemps, Caroline; Carrier, Alice; Dagorn, Jean–Charles; Pébusque, Marie‐Josèphe; Iovanna, Juan; Dusetti, Nelson

doi:10.1038/sj.onc.1208951

Cited by 123 publications

(123 citation statements)

References 39 publications

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“…In a search for the mechanism of apoptosis in the absence of p53, we found that EGCG treatment induced the expression of p73 but not p63 and that inactivation of p73 protects cells from EGCG-induced apoptosis. The results of our study are consistent with previous reports that p73 is sufficient to induce apoptosis in cells lacking functional p53 (36)(37)(38). However, there is no notable difference in the expression levels of p73 between SHP-2 WT and mutant cells, although there are remarkable differences in apoptosis and expression of target genes.…”

Section: Discussionsupporting

confidence: 83%

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

Amin¹,

Thakur²,

Paul³

et al. 2007

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

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Green tea polyphenol, epigallocatechin-3-gallate (EGCG) differentially regulates the cellular growth of cancer cells in a p53-dependent manner through apoptosis and/or cell cycle arrest. In an effort to further elucidate the mechanism of differential growth regulation by EGCG, we have investigated the role of the tyrosine phosphatase, SHP-2. Comparing the responses of mouse embryonic fibroblasts (MEFs), expressing either WT or functionally inactive/truncated SHP-2, we find that inactivation of SHP-2 remarkably sensitizes cells to EGCG-mediated killing. MEFs lacking functional SHP-2 undergo massive apoptosis upon treatment with EGCG. By comparing gene expression profiles, we have identified a set of transcriptional targets of p53 that are differentially modulated in cells undergoing apoptosis. Western blot and real-time PCR analyses of a select group of genes further confirm that the expression is SHP-2-dependent. Similar observations were made in MEFs lacking p53, confirming that the expression of these ''p53 target genes'' is p53-independent. In addition, EGCG treatment induced the expression of p73 mRNA and protein in both cell types, but not p63. Inactivation of p73 in cells expressing nonfunctional SHP-2 markedly inhibited apoptosis and p53 target gene expression. Although phosphorylation of JNK is differentially regulated by SHP2, it was found to be dispensable for EGCG-induced apoptosis and p53 target gene expression. Our results have identified SHP-2 as a negative regulator of EGCG-inducedapoptosis and have identified a subset of p53 target genes whose expression is paradoxically not mediated by p53 but by one of its family members, p73.green tea ͉ MAPK pathway ͉ mouse embryonic fibroblasts ͉ transcriptional activation

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Section: Discussionsupporting

confidence: 83%

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

Amin¹,

Thakur²,

Paul³

et al. 2007

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

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“…Further evidence of the proliferative actions of ERa is that the most strongly ERa-downregulated gene was the cell cycle repressor TP53INP1, a downregulation that was opposed by ERb. Increase of TP53INP1 leads to cycle arrest in G 1 and enhanced p53-mediated apoptosis (Tomasini et al, 2005). In addition, several antiproliferative genes (QSCN6, NDRG3, SEPT9, KCTD11 and STK3) are affected by ERb alone, strongly supporting the notion that ERb is antiproliferative and capable of inhibiting or reducing the growth of tumors.…”

Section: Antiproliferative and Antitumorigenic Actions Of Erbmentioning

confidence: 71%

A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells

et al. 2007

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“…Cisplatin is a strong, widely used anti-cancer therapeutic drug that causes DNA damage and programmed cell death and is activated in a p53-independent pathway [35,36] . Here, we have demonstrated that with the treatment of cisplatin, expression levels of cleaved Caspase-3 and PARP were elevated and accompanied by increased migfilin expression.…”

Section: Discussionmentioning

confidence: 99%

Migfilin sensitizes cisplatin-induced apoptosis in human glioma cells in vitro

Fan

et al. 2012

Acta Pharmacol Sin

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Aim: Filamin binding LIM protein 1, also known as migfilin, is a skeleton organization protein that binds to mitogen-inducible gene 2 at cell-extracellular matrix adhesions. The aim of this study was to investigate the role of migfilin in cisplatin-induced apoptosis in human glioma cells, to determine the functional domains of migfilin, and to elucidate the molecular mechanisms underlying the regulation of cisplatin-related chemosensitivity. Methods: The human glioma cell lines Hs683, H4, and U-87 MG were transfected with pEGFP-C2-migfilin to elevate the expression level of migfilin. RNA interference was used to reduce the expression of migfilin. To determine the functional domains of migfilin, U-87 MG cells were transfected with plasmids of migfilin deletion mutants. After treatment with cisplatin (40 µmol/L) for 24 h, the cell viability was assessed using the MTS assay, and the cell apoptotic was examined using the DAPI staining assay and TUNEL analysis. Expression levels of apoptosis-related proteins were detected by Western blot analysis. Results: Overexpression of migfilin significantly enhanced cisplatin-induced apoptosis in Hs683, H4, and U-87 MG cells, whereas downregulation of migfilin expression inhibited the chemosensitivity of these cell lines. The N-terminal region of migfilin alone was able to enhance the cisplatin-induced apoptosis. However, despite the existence of the N-terminal region, mutants of migfilin with any one of three LIM domains deleted led to a function loss. Furthermore, apoptotic proteins (PARP and caspase-3) and the anti-apoptotic protein Bcl-xL were modulated by the expression level of migfilin in combination with cisplatin. Conclusion: The LIM1-3 domains of migfilin play a key role in sensitizing glioma cells to cisplatin-induced apoptosis through regulation of apoptosis-related proteins.

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TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activity

Cited by 123 publications

References 39 publications

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells

Migfilin sensitizes cisplatin-induced apoptosis in human glioma cells in vitro

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