Induction of EMT by Twist Proteins as a Collateral Effect of Tumor-Promoting Inactivation of Premature Senescence

Ansieau, Stéphane; Bastid, Jérémy; Doreau, Agnès; Morel, Anne; Bouchet, Benjamin Pierre; Thomas, Clémence; Fauvet, Frédérique; Puisieux, Isabelle; Doglioni, Claudio; Piccinin, Sara; Maestro, Roberta; Voeltzel, Thibault; Selmi, Abdelkader; Valsesia‐Wittmann, Sandrine; Fromentel, Claude Caron de; Puisieux, Alain

doi:10.1016/j.ccr.2008.06.005

Cited by 631 publications

(607 citation statements)

References 41 publications

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“…The significant reduction in G0/ G1 arrest observed in cells expressing wild-type Twist-1 or the S42E Twist-1 mutant but not in S42A Twist-1 cells provides a functional read out of the inhibitory effect of Twist-1 phosphorylation on the key cell-cycle effector p21 Waf1 . Indeed, Twist-1 was shown to override premature senescence through inhibition of p16 INK4A and p21 Waf1 promoter activation induced by H-Ras V12 and p53 in E1A-immortalized MEFs; however, the molecular mechanisms involved in this effect are still under investigation (Ansieau et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage

et al. 2010

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Protein kinase B (PKB/Akt) is ubiquitously expressed in cells. Phosphorylation of its multiple targets in response to various stimuli, including growth factors or cytokines, promotes cell survival and inhibits apoptosis. PKB is upregulated in many different cancers and a significant amount of the enzyme is present in its activated form. Here we show that PKB phosphorylates one of the anti-apoptotic proteins-transcription factor Twist-1 at Ser42. Cells expressing Twist-1 displayed inefficient p53 upregulation in response to DNA damage induced by c-irradiation or the genotoxic drug adriamycin. This influenced the activation of p53 target genes such as p21 Waf1 and Bax and led to aberrant cell-cycle regulation and the inhibition of apoptosis. The impaired induction of these p53 effector molecules is likely to be mediated by PKB-dependent phosphorylation of Twist-1 because, unlike the wild-type mutant, the Twist-1 S42A mutant did not confer cell resistance to DNA damage. Moreover, phosphorylation of Twist-1 at Ser42 was shown in vivo in various human cancer tissues, suggesting that this posttranslational modification ensures functional activation of Twist-1 after promotion of survival during carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage

et al. 2010

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“…Like replicative senescence, oncogene-induced premature senescence is identified by senescence biomarkers such as senescenceassociated b-galactosidase (SA-b-gal) (Dimri et al, 1995), and is accompanied by increased expression of negative growth regulators including p53, p21 WAF1 and p16 INK4A (Bandyopadhyay et al, 2001;Bennett, 2003;Ohtani et al, 2004;Takahashi et al, 2006;Haferkamp et al, 2008). Several recent studies have shown that oncogene-induced premature senescence indeed occurs in premalignant human tumors and provides an initial barrier to tumor genesis in vivo (Hornsby, 2007;Acosta et al, 2008;Ansieau et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

Wang

Liu

et al. 2010

Oncogene

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Oncogene-mediated premature senescence has emerged as a potential tumor-suppressive mechanism in early cancer transitions. Many studies showed that Ras and p38 mitogen-activated protein kinase (MAPK) participate in premature senescence. Our previous work indicated that the HMG box-containing protein 1 (HBP1) transcription factor is involved in Ras-and p38 MAPK-induced premature senescence, but the mechanism of which has not yet been identified. Here, we showed that the p16 INK4A cyclin-dependent kinase inhibitor is a novel target of HBP1 participating in Ras-induced premature senescence. The promoter of the p16 INK4A gene contains an HBP1-binding site at position À426 to À433 bp from the transcriptional start site. HBP1 regulates the expression of the endogenous p16 INK4A gene through direct sequence-specific binding. With HBP1 expression and the subsequent increase of p16 INK4A gene expression, Ras induces premature senescence in primary cells. The data suggest a model in which Ras and p38 MAPK signaling engage HBP1 and p16 INK4A to trigger premature senescence. In addition, we report that HBP1 knockdown is also required for Ras-induced transformation. All the data indicate that the mechanism of HBP1-mediated transcriptional regulation is important for not only premature senescence but also tumorigenesis.

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“…Both proteins may act with oncoproteins, such as Ras or ErbB2, leading to EMT in epithelial cells [17]. In conjunction with hypoxia-inducible factor-2a and SIP1, Twist 2 has been suggested to correlate with metastasis in adenoid cystic carcinoma [18].…”

Section: Discussionmentioning

confidence: 99%

Epithelial–Mesenchymal Transition Protein Expression in Basal Cell Adenomas and Basal Cell Adenocarcinomas

Tesdahl

Wilson

Hoffman

et al. 2015

Head and Neck Pathol

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Basal cell adenomas and basal cell adenocarcinomas show marked histomorphologic similarity and are separated microscopically primarily by the invasive characteristics of the adenocarcinomas. We wished to explore potential differences in the expression of epithelial-mesenchymal transition associated proteins in these two tumor types. A tissue microarray was constructed utilizing 29 basal cell adenomas and 16 basal cell adenocarcinomas. Immunohistochemical expression of E-cadherin, betacatenin, Twist 1 and vimentin were investigated. Both tumors expressed all proteins in a relatively similar manner. Nuclear beta-catenin was essentially limited to the abluminal cell populations in both tumor types. E-cadherin was limited largely to luminal locations but was more prevalent in the adenocarcinomas as compared to the adenomas. Primarily abluminal expression for vimentin was seen, sometimes present in an apical dot-like pattern. Distinct populations of cellular expression of these four markers of epithelial mesenchymal transition were present but were similar in locations in both tumors with no patterns discerned to separate basal cell adenoma from basal cell adenocarcinoma. Given these findings, the mechanisms by which basal cell adenocarcinoma is able to invade while its counterpart, basal cell adenoma can not, may be more complex than in other tumor types.

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Induction of EMT by Twist Proteins as a Collateral Effect of Tumor-Promoting Inactivation of Premature Senescence

Cited by 631 publications

References 41 publications

PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage

PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

Epithelial–Mesenchymal Transition Protein Expression in Basal Cell Adenomas and Basal Cell Adenocarcinomas

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