Twist and p53 reciprocally regulate target genes via direct interaction

Shiota, Masaki; Izumi, Hiroto; Onitsuka, Takamitsu; Miyamoto, Naoya; Kashiwagi, Eiji; Kidani, Akihiko; Hirano, Gen; Takahashi, Mamoru; Naito, Seiji; Kohno, Kimitoshi

doi:10.1038/onc.2008.176

Cited by 116 publications

(115 citation statements)

References 32 publications

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“…[14][15][16] The protein concentrations were determined using a Protein Assay Kit (Bio-Rad, Hercules, CA, USA) based on Bradford's method. Whole-cell extracts (30 mg) were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to polyvinylidine difluoride microporous membranes (Micron Separations, Westborough, MA, USA) using a semidry blotter.…”

Section: Western Blottingmentioning

confidence: 99%

“…[14][15][16] The following doublestranded RNA 25-basepair oligonucleotides were commercially generated (Invitrogen): 5 0 -AAGUGAG CGAAACUGUUUCCAAGGC-3 0 (sense) and 5 0 -GCCU UGGAAACAGUUUCGCUCACUU-3 0 (antisense) for GNMT siRNA #1; 5 0 -AUGUUGUGACGUCCUUGGU CAAGUC-3 0 (sense) and 5 0 -GACUUGACCAAGGAC GUCACAACAU-3 0 (antisense) for GNMT siRNA #2. RWPE-1, PC-3, and LNCaP cells were transfected with the indicated amounts of siRNA using Lipofectamine 2000 (Invitrogen) according to the manufacturer's protocol.…”

Section: Knockdown Analysis Using Sirnasmentioning

confidence: 99%

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The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer

et al. 2011

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Glycine N-methyltransferase (GNMT) has a role in the metabolism of methionine as well as in gluconeogenesis. It has recently been reported that the GNMT gene acts as a tumor-susceptible gene. However, little is known about the specific function of GNMT in carcinogenesis and malignant progression. To better our understanding of the function of GNMT in prostate cancer, we used siRNAs to examine the effects of GNMT knockdown on cell proliferation and the cell cycle. In addition, the relation between immunohistochemical GNMT expression and clinicopathologic parameters was investigated in 148 prostate cancer tissues. Here, we show that siRNAmediated GNMT knockdown results in an inhibition of proliferation, and induces G1 arrest and apoptosis in prostate cancer cell lines. Moreover, high cytoplasmic GNMT expression was also correlated with a higher Gleason score (Po0.001) and higher pT stage (P ¼ 0.027). The patients with high GNMT cytoplasmic expression showed significantly lower disease-free survival rates than patients with low expression (Po0.001). High GNMT cytoplasmic expression had a significant impact on patient disease-free survival in multivariate analysis (P ¼ 0.005). This is the first investigation to reveal the novel finding that GNMT may have an important role in promoting prostate cancer cell growth via the regulation of apoptosis and contribute to the progression of prostate cancer. The modulation of GNMT expression or function may be a strategy for developing novel therapeutics for prostate cancer. GNMT may represent a novel marker of malignant progression and poor prognosis in prostate cancer.

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Section: Western Blottingmentioning

confidence: 99%

Section: Knockdown Analysis Using Sirnasmentioning

confidence: 99%

The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer

et al. 2011

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“…76 Several other mechanisms may also contribute to the p53-inhibitory activity of TWIST1, including inhibition of acetyltransferases that serve as transcriptional coactivators for p53, 77 modulation of the activity of a transactivator of the TP53 promoter, 78 prevention of p53 phosphorylation, 78 and direct suppression of the DNA-binding activity of p53. 79 Of note, the TWIST1 and TWIST2 proteins have also recently been shown to prevent oncogene-induced premature senescence with concomitant abrogation of p16 INK4a and p21 WAF1/CIP1 activation, and to induce, in cooperation with activated mitogenic oncoproteins, epithelial-mesenchymal transition, suggesting a role as general inhibitors of multiple oncogene-induced safeguard programs. 80 Inactivation of the p14 ARF -p53 Pathway by BMI1…”

Section: Transactivation Of Mdm2 Expression By Mycnmentioning

confidence: 99%

Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14ARF-MDM2-p53 axis

et al. 2009

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A primary failsafe program against unrestrained proliferation and oncogenesis is provided by the p53 tumor suppressor protein, inactivation of which is considered as a hallmark of cancer. Intriguingly, mutations of the TP53 gene are rarely encountered in neuroblastoma tumors, suggesting that alternative p53-inactivating lesions account for escape from p53 control in this childhood malignancy. Several recent studies have shed light on the mechanisms by which neuroblastoma cells circumvent the p53-driven antitumor barrier. We review here these mechanisms for evasion of p53-mediated growth control and conclude that deregulation of the p14 ARF -MDM2-p53 axis seems to be the principal mode of p53 inactivation in neuroblastoma, opening new perspectives for targeted therapeutic intervention. The p53 tumor surveillance network constitutes the core defense mechanism of the cell against loss of genomic integrity and malignant transformation. Evasion of p53 activity is, therefore, a prerequisite for tumor cells to survive and thrive, and this is attainable either through mutation of the TP53 gene or through defects in the molecular components that govern or execute the various aspects of the p53 response. Elucidation of the mechanisms by which tumor cells override the p53-orchestrated failsafe program is not only important to gain insight into the ontogenesis of a tumor, but may also point to preferable modes of therapeutic intervention.A striking feature of the childhood cancer neuroblastoma is the low frequency (o2%) of TP53 mutations at diagnosis. 1 There is considerable evidence that TP53 mutations may be acquired during chemotherapy and malignant progression of neuroblastoma. 1-4 Accordingly, an increased frequency of TP53 mutations is observed in multidrug-resistant neuroblastoma cell lines and in neuroblastoma cell lines established at relapse, but even in this context, the majority of cell lines remain characterized by a wild-type TP53 gene. 5,6 Furthermore, many studies indicate that the p53 signal transduction pathway is intrinsically intact in neuroblastoma, 1,4,7-9 suggesting that circumvention of the p53 barrier in this tumor entity relies primarily on an inappropriately increased activity of inhibitors of p53 signaling or, alternatively, on a loss of positive regulators of p53 activity. This review summarizes our current understanding of the mechanisms by which neuroblastoma cells escape from p53-mediated tumor surveillance and positions deregulation of the p14 ARF -MDM2-p53 axis as a central switch for p53 inactivation in neuroblastoma.The p14 ARF -MDM2-p53 Axis and Lesions at the MDM2 and CDKN2A (p16 INK4a /p14 ARF ) Loci in NeuroblastomaThe MDM2 oncoprotein, a human homolog of the 'mouse double minute 2' gene product that was originally identified in a spontaneously transformed mouse cell line with double minute chromosomes, 10 is a critical negative regulator of p53 stability and activity. It has been well established that p53 and MDM2 mutually control their cellular levels and form a tight autoregulatory...

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“…Twist1 prevents activation of p53 through multiple mechanisms, such as down-regulation of alternative reading frame protein (ARF), 15 and through direct interactions. 49 Further experiments will be necessary to determine what role p53 plays in RLFs following Twist1 depletion.…”

Section: Pulmonary Fibrosis and Twist1mentioning

confidence: 99%

Gene Expression Profiling of Pulmonary Fibrosis Identifies Twist1 as an Antiapoptotic Molecular “Rectifier” of Growth Factor Signaling

Bridges

Kass

Loh

et al. 2009

The American Journal of Pathology

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Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease. To gain insight into IPF pathogenesis, we performed gene expression profiling of IPF lungs. Twist1, a basic helix-loop-helix protein, was found among the most consistently and highly up-regulated genes and was expressed in nuclei of type II epithelial cells, macrophages, and fibroblasts in IPF lungs. We studied the function of Twist1 in fibroblasts further, because they are the major effector cells in this disease and persist despite an ambient proapoptotic environment. Twist1 was induced by the profibrotic growth factors (GFs) basic fibroblast growth factor, platelet-derived growth factor, and epidermal growth factor in primary rat lung fibroblasts (RLFs). Suppression of Twist1 expression resulted in decreased RLF accumulation due to increased apoptosis, whereas Twist1 overexpression protected RLFs against several apoptotic stimuli. Addition of platelet-derived growth factor in combination with other GFs led to an increase in proliferation. When Twist1 was depleted, GFs continued to act as mitogens but caused a marked increase in cell death. The increase in apoptosis under basal or growth factorstimulated conditions was partly mediated by up-regulation of the proapoptotic Bcl-2 family members, Bim and PUMA. These findings indicate that Twist1 promotes survival and accumulation of fibroblasts by shaping their responsiveness to growth factor stimulation. We propose that Twist1 represents one of the factors that promotes pathogenic accumulation of fibroblasts in fibrotic lung disease. (Am J Pathol

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Twist and p53 reciprocally regulate target genes via direct interaction

Cited by 116 publications

References 32 publications

The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer

The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer

Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14ARF-MDM2-p53 axis

Gene Expression Profiling of Pulmonary Fibrosis Identifies Twist1 as an Antiapoptotic Molecular “Rectifier” of Growth Factor Signaling

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