Integrated high-throughput analysis identifies Sp1 as a crucial determinant of p53-mediated apoptosis

Li, H; Zhang, Y; Ströse, Anda Jana; Tedesco, Donato; Gurova, Katerina V.; Selivanova, Galina

doi:10.1038/cdd.2014.69

Cited by 59 publications

(66 citation statements)

References 34 publications

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“…Repression of anti-apoptotic/survival genes in addition with induction of pro-apoptotic targets was shown to critically control the apoptotic outcome of RITA-treated cancer cells. 34,[58][59][60] In glioma cells, we found that Nutlin-3a behaved as shown previously for RITA regarding the p53 transcriptional repression activity. 34 However, high expression of α5β1 integrin conferred another anti-apoptotic signaling, which we identified to be in part supported by PEA-15.…”

Section: Discussionsupporting

confidence: 86%

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

et al. 2015

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Integrin α5β1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5β1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer therapy. However, p53-dependent apoptosis is not always achieved by p53-reactivating compounds such as Nutlin-3a, although full transcriptional activity of p53 could be obtained. Here we investigated whether integrin α5β1 functional inhibition or repression could sensitize glioma cells to Nutlin-3a-induced p53-dependent apoptosis. We discovered that α5β1 integrin-specific blocking antibodies or small RGD-like antagonists in association with Nutlin-3a triggered a caspase (Casp) 8/Casp 3-dependent strong apoptosis in glioma cells expressing a functional p53. We deciphered the molecular mechanisms involved and we showed the crucial role of two anti-apoptotic proteins, phosphoprotein enriched in astrocytes 15 (PEA-15) and survivin in glioma cell apoptotic outcome. PEA-15 is under α5β1 integrin/AKT (protein kinase B) control and survivin is a p53-repressed target. Moreover, interconnections between integrin and p53 pathways were revealed. Indeed PEA-15 repression by specific small-interfering RNA (siRNA)-activated p53 pathway to repress survivin and conversely survivin repression by specific siRNA decreased α5β1 integrin expression. This pro-apoptotic loop could be generalized to several glioma cell lines, whatever their p53 status, inasmuch PEA-15 and survivin protein levels were decreased. Our findings identify a novel mechanism whereby inhibition of α5β1 integrin and activation of p53 modulates two anti-apoptotic proteins crucially involved in the apoptotic answer of glioma cells. Importantly, our results suggest that high-grade glioma expressing high level of α5β1 integrin may benefit from associated therapies including integrin antagonists and repressors of survivin expression.

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Section: Discussionsupporting

confidence: 86%

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

et al. 2015

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“…For example, cell cycle genes were preferentially enriched for the middle to late phases during the time course, consistent with the finding of enriched cell cycle regulator motifs in the promoters of these genes, e.g., the E2F1, c-MYC, HIF-1a, and MITF genes (82)(83)(84)(85)(86). The middle and late categories were also enriched for stress response genes, which is consistent with the motif enrichments of factors involved in stress responses, such as E2F7, HIF-1a, and SP1 (87)(88)(89)(90). Furthermore, gene promoters of each category were enriched for motifs related to circadian rhythm.…”

Section: Discussionsupporting

confidence: 72%

Identifying Novel Transcriptional Regulators with Circadian Expression

Schick

Becker

Thakurela

et al. 2016

Molecular and Cellular Biology

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Organisms adapt their physiology and behavior to the 24-h day-night cycle to which they are exposed. On a cellular level, this is regulated by intrinsic transcriptional-translational feedback loops that are important for maintaining the circadian rhythm. These loops are organized by members of the core clock network, which further regulate transcription of downstream genes, resulting in their circadian expression. Despite progress in understanding circadian gene expression, only a few players involved in circadian transcriptional regulation, including transcription factors, epigenetic regulators, and long noncoding RNAs, are known. Aiming to discover such genes, we performed a high-coverage transcriptome analysis of a circadian time course in murine fibroblast cells. In combination with a newly developed algorithm, we identified many transcription factors, epigenetic regulators, and long intergenic noncoding RNAs that are cyclically expressed. In addition, a number of these genes also showed circadian expression in mouse tissues. Furthermore, the knockdown of one such factor, Zfp28, influenced the core clock network. Mathematical modeling was able to predict putative regulator-effector interactions between the identified circadian genes and may help for investigations into the gene regulatory networks underlying circadian rhythms.O rganisms adapt to the 24-h day-night cycle, which leads to oscillations in physiology and behavior. This is coordinated by an intrinsic molecular clock originating from the interplay of transcriptional-translational feedback loops (1). In mammals, the core loop consists of the transcriptional activators Clock and Bmal1 and the repressors Period (Per) and cryptochrome (Cry). In a second loop, retinoid-related orphan receptors (ROR) activate transcription while Rev-Erb factors (Nr1d1 and Nr1d2) repress transcription (2). These core clock components also regulate the expression of additional genes, possibly resulting in an oscillating transcription of these socalled clock-controlled genes and finally in the circadian phenotype.Recent genome-wide studies of circadian time courses in various mouse tissues indicated that each tissue expresses its own particular set of cyclical genes, which only partly overlap each other (3-7). Nearly half of all genes in the mouse genome show circadian oscillation in at least one tissue (7). The basic mechanisms causing transcriptional rhythms of the core clock components are similar among all tissues, but how tissue-specific circadian output is achieved remains unknown, although several mechanisms have been proposed (2). Among these are the use of tissue-specific transcription factors (TFs) or coregulators (6,8) and different temporal control of RNA polymerase II recruitment (9, 10), as well as defined rhythms in histone modifications accompanied by differential gene regulation (9-19).To gain further insight into the transcriptional control of the circadian rhythm, we aimed to identify novel factors, particularly transcription factors and epigenetic regula...

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“…A genome-wide analysis of chromatin occupancy by p53 and a parallel analysis of gene expression have identified Sp1 as one of the p53 modulators that confer specificity to p53-mediated transcriptional response upon induction of tumor cell apoptosis (Nikulenkov, et al, 2012). Although Sp1 could be indispensable for the proapoptotic transcriptional repression by p53, it is not for the induction of pro-apoptotic genes (Li, et al, 2014a).…”

Section: Sp1 Is Involved In Cell Growth and Tumorigenesismentioning

confidence: 99%