SW480, a p53 Double-mutant Cell Line Retains Proficiency for Some p53 Functions

Rochette, Patrick J.; Bastien, Nathalie; Lavoie, Josée; Guérin, Sylvain L.; Drouin, Régen

doi:10.1016/j.jmb.2005.06.033

Cited by 81 publications

(66 citation statements)

References 55 publications

(75 reference statements)

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“…SW480 cells contain a mutated form of p53, presumably without proapoptotic potential but with some transcriptional activity such as the ability to induce p21 (29). In line with this, we could not find increased apoptosis in the ERh-expressing tumor xenografts, but a strong induction of p21-protein in vitro.…”

Section: Resultssupporting

confidence: 78%

Tumor Repressive Functions of Estrogen Receptor β in SW480 Colon Cancer Cells

et al. 2009

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Estrogen receptor B (ERB) is the predominant ER in the colorectal epithelium. Compared with normal colon tissue, ERB expression is reduced in colorectal cancer. Our hypothesis is that ERB inhibits proliferation of colon cancer cells. Hence, the aim of this study has been to investigate the molecular function of ERB in colon cancer cells, focusing on cell cycle regulation. SW480 colon cancer cells have been lentivirus transduced with ERB expression construct with or without mutated DNA-binding domain or an empty control vector. Expression of ERB resulted in inhibition of proliferation and G 1 phase cell cycle arrest and this effect was dependent on a functional DNA-binding region. c-Myc is overexpressed in an overwhelming majority of colorectal tumors. By Western blot and real-time PCR, we found c-Myc to be down-regulated in the ERB-expressing cells. Furthermore, the c-Myc target gene p21 (Waf1/Cip1) was induced and Cdc25A was reduced by ERB at the transcriptional level. The second cdk2-inhibitor, p27 Kip1 , was induced by ERB, but this regulation occurred at the posttranscriptional level, probably through ERB-mediated repression of the F-box protein p45 Skp2 . Expression of the ERB-variant with mutated DNA binding domain resulted in completely different cell cycle gene regulation. We performed in vivo studies with SW480 cells F ERB transplanted into severe combined immunodeficient/beige mice; after three weeks of ERB-expression, a 70% reduction of tumor volume was seen. Our results show that ERB inhibits proliferation as well as colon cancer xenograft growth, probably as a consequence of ERB-mediated inhibition of cell-cycle pathways. Furthermore, this ERB-mediated cell cycle repression is dependent on functional ERE binding. [Cancer Res 2009;69(15):6100-6]

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Section: Resultssupporting

confidence: 78%

Tumor Repressive Functions of Estrogen Receptor β in SW480 Colon Cancer Cells

et al. 2009

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“…Immunofluorescence was done as described previously using the primary DO-1 mouse anti-p53 antibody (Santa Cruz Biotechnology) and the secondary goat anti-mouse antibody labeled with Alexa Fluor 488 (Invitrogen) diluted at 1:250 and 1:500, respectively (30). Fluorescence quantification and cell cycle data were obtained by laser scanning cytometry.…”

Section: Methodsmentioning

confidence: 99%

p53 Pre- and Post-Binding Event Theories Revisited: Stresses Reveal Specific and Dynamic p53-Binding Patterns on the p21 Gene Promoter

et al. 2009

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Abstractp53 is a master transcription factor that prevents neoplasia and genomic instability. It is an important target for anticancer drug design. Understanding the molecular mechanisms behind its transcriptional activities in normal cells is a prerequisite to further understand the deregulation effected by mutant p53 in cancerous cells. Currently, how p53 coordinates transcription programs in response to stress remains unclear. One theory proposes that stresses induce pre-binding events that direct p53 to bind to specific response elements, whereas a second posits that, in response to stress, p53 binds most response elements and post-binding events then regulate transcription initiation. It is critical to establish the relevance of both theories and investigate whether stresses induce specific p53-binding patterns correlated with effector gene induction. Using unique in cellulo genomic footprinting experiments, we studied p53 binding to the five response elements of p21 in response to stresses and monitored p21 mRNA variant transcription. We show clear footprints of p53 bound to response elements in living cells and reveal that the binding of p53 to response elements is transient, subject to dynamic changes during stress responses, and influenced by response element pentamer orientations. We show further that stresses lead to specific p53-binding patterns correlated with particular p21 mRNA variant transcription profiles and that p53 binding is necessary but not sufficient to induce p21 transcription. Our results indicate that pre-and post-binding events act together to regulate adapted stress responses; this paves the way to the unification of pre-and post-binding event theories.

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“…In sW620 cells, p53 protein carries two mutations, which do not affect its ability to bind to DnA (21). In the present study we show that, in spite of these mutations, transcription and protein expression of mutated-p53 were up-regulated by p38 in lupulone-treated sW620 cells.…”

Section: Discussionmentioning

confidence: 38%

Lupulone triggers p38 MAPK-controlled activation of p53 and of the TRAIL receptor apoptotic pathway in human colon cancer-derived metastatic cells

Raul

2011

Oncol Rep

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Abstract. We previously reported that the chemopreventive agent lupulone induces apoptosis through activation of the extrinsic pathway via trAIl Dr4/Dr5 death receptors overcoming sW620 cell resistance to trAIl. However, the underlying molecular mechanisms remain unknown. since the mitogen-activated protein kinases (MApKs), Jun n-terminal kinase (JnK), extracellular signal-regulated kinase (erK) and p38 control fundamental cellular processes such as apoptosis, we determined the role of these MApKs in lupulone-triggered apoptosis. We analyzed the effects of JnK, erK and p38 MApK inhibitors on lupulone-induced apoptosis by flow cytometry using specific antibodies and real-time RT-PCR. our data showed that among the MApKs, only p38 played a major role in lupulone-triggered apoptosis. In contrast to JnK and ERK inhibition, the specific inactivation of p38 inhibited the lupulone-triggered up-regulation of p53 and trAIl-death receptor Dr4/Dr5 expression, and prevented DnA fragmentation. lupulone treatment enhanced the expression of the anti-apoptotic Mcl-1 protein by 60% favoring the preservation of mitochondrial integrity. the inactivation of p38 initiated a 50% reduction in Mcl-1, Bcl-2 and Bax expression without changing the Mcl-1/Bax ratio suggesting that p38 was not involved in the protective effect of lupulone on mitochondria. our data support the view that the lupulone-triggered enhanced expression of p38 plays a major role in the activation of p53 and of the trAIl-death receptor apoptotic pathway in sW620 human colon cancer-derived metastatic cells.

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SW480, a p53 Double-mutant Cell Line Retains Proficiency for Some p53 Functions

Cited by 81 publications

References 55 publications

Tumor Repressive Functions of Estrogen Receptor β in SW480 Colon Cancer Cells

Tumor Repressive Functions of Estrogen Receptor β in SW480 Colon Cancer Cells

p53 Pre- and Post-Binding Event Theories Revisited: Stresses Reveal Specific and Dynamic p53-Binding Patterns on the p21 Gene Promoter

Lupulone triggers p38 MAPK-controlled activation of p53 and of the TRAIL receptor apoptotic pathway in human colon cancer-derived metastatic cells

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