p21 Gene Expression Is Modulated by Egr1

Ragione, Fulvio Della; Cucciolla, Valeria; Criniti, Vittoria; Indaco, Stefania; Borriello, Adriana; Zappia, Vincenzo

doi:10.1074/jbc.m300771200

Cited by 81 publications

(25 citation statements)

References 67 publications

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“…Transcription factor pulldown assays were done as described (18). Briefly, two doublestranded oligonucleotides corresponding to positions Ϫ388 to Ϫ364 of the human MDM2 P2 promoter and containing biotin on the 5Ј nucleotide were incubated with 200 g of JF cell nuclear lysate for the pull-down assays (see Supporting Text for details).…”

Section: Methodsmentioning

confidence: 99%

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The p53 regulatory geneMDM2is a direct transcriptional target of MYCN in neuroblastoma

Slack

Chen

Tonelli

et al. 2005

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

211

183

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The MYCN oncogene is the major negative prognostic marker in neuroblastoma with important roles in both the pathogenesis and clinical behavior of this aggressive malignancy. MYC oncogenes activate both proliferative and apoptotic cellular pathways and, accordingly, inhibition of p53-mediated apoptosis is a prerequisite for MYC-driven tumorigenesis. To identify novel transcriptional targets mediating the MYCN-dependent phenotype, we screened a MYCN-amplified neuroblastoma cell line by using chromatin immunoprecipitation (ChIP) cloning. We identified the essential p53 inhibitor and protooncogene MDM2 as a putative target. (1), and improvement in outcome clearly requires a better understanding of the pathogenesis and pathophysiology of this disease. The MYCN oncogene is amplified in 25% of neuroblastomas and is the most powerful clinical prognostic marker for poor survival (2). Tissue-targeted expression of MYCN is sufficient to induce neuroblastoma in transgenic mice (3), suggesting this oncogene plays an important role in the pathogenesis of neuroblastoma. In vitro studies demonstrate that MYCN overexpression induces an aggressive phenotype with decreased contact inhibition, decreased growth factor dependence, and increased metastatic potential (4, 5). These findings correlate with the malignant clinical behavior of MYCN-amplified tumors in children.MYCN is a transcription factor with well defined mechanisms of both transcriptional activation, when bound to promoter E-boxes as a MYCN͞Max heterodimer, and transcriptional repression, when bound as a heterodimer with Mnt, Mxi, Mad, or other negative cofactors (6, 7). MYCN is involved in many aspects of normal and oncogenic cellular physiology, including proliferation, cell cycle regulation, apoptosis, and genomic instability (8, 9). Clinically and therapeutically relevant insight into neuroblastoma biology thus can be achieved through identification of the downstream transcriptional targets of MYCN involved in these pathways.In vitro studies of neuroblastoma cell lines demonstrate that overexpression of MYCN induces the conflicting cellular processes of rapid proliferation and apoptotic cell death (10). MYCN shortens the G 1 -S phase transition, increases cell proliferation rates, and decreases cell dependence on paracrine growth factors (5,11,12). Concurrently, MYCN suppresses Bcl-2, activates Bax, and sensitizes cells to genotoxicity-mediated apoptosis through intrinsic apoptosis pathways (13). MYCC has been shown to activate the ARF tumor suppressor, leading to p53 activation and apoptosis through Bcl-x and Bcl-2-dependent and -independent pathways (14). Less than 2% of neuroblastomas have mutated p53, and the p53 pathways are functionally active in the majority of de novo tumors (15, 16). Therefore, for MYCN-expressing neuroblastoma precursor cells to escape p53-mediated cell death, proliferate, and progress to invasive malignancy, a balance must be struck between MYCN-driven proliferation and MYCN-driven apoptosis.In this study we use chromatin immunoprecipita...

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Section: Methodsmentioning

confidence: 99%

“…18). This method uses streptavidin beads to precipitate biotin-labeled double-stranded oligonucleotides homologous to the promoter element of interest and any associated DNA binding transcription factors.…”

Section: Mycn Binds the E-box Element Of The Mdm2 Promoter In Vitromentioning

confidence: 99%

The p53 regulatory geneMDM2is a direct transcriptional target of MYCN in neuroblastoma

Slack

Chen

Tonelli

et al. 2005

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

211

183

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“…At a molecular level, resveratrol up-regulates p53 expression and induces nuclear translocation of p53, leading to the induction of p21 [130][131][132], but p53 is not the only factor by which resveratrol activates p21. Indeed, resveratrol can up-regulate p21 Cip1 transcription through a selective up-regulation of the transcription factor Egr-1 [133]. This up-regulation is an Erk1/2-dependent mechanism which induces a binding of Erg-1 in vitro and in vivo to the consensus sequence of the p21 promoter [133].…”

Section: Kip1mentioning

confidence: 99%

“…Indeed, resveratrol can up-regulate p21 Cip1 transcription through a selective up-regulation of the transcription factor Egr-1 [133]. This up-regulation is an Erk1/2-dependent mechanism which induces a binding of Erg-1 in vitro and in vivo to the consensus sequence of the p21 promoter [133]. p53-inductible p21 CIP1 and p27 Kip1 can induce G1 arrest by inhibiting the cyclin D, E and A -cdk complex, while INK4 proteins antagonize only the cyclin D-cdk complex.…”

Section: Kip1mentioning

confidence: 99%

Resveratrol as a Chemopreventive Agent: A Promising Molecule for Fighting Cancer

Delmas¹,

Lançon²,

Colin³

et al. 2006

CDT

355

223

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“…The polyclonal antibodies to p l6 Ink4A, p2l Cip1 and actin were from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Cell extracts and immunoblotting analyses for cyclin-dependent kinase inhibitors were performed as described (17).…”

Section: Cell Cycle Analysismentioning

confidence: 99%

Acetylsalicylic Acid Inhibits Proliferation of Human Bone Marrow Stromal Cells and Matrix Mineralization

Guida

Annunziata

Passaro³

et al. 2008

Int J Immunopathol Pharmacol

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Acetylsalicylic acid (ASA) and other non-steroidal anti-inflammatory drugs have been shown to potentially inhibit bone healing and bone formation in both animal and clinical studies. Due to the extensive diffusion of ASA-based long-term therapies, the implications of such a side-effect are of interest in all types of bone surgery, including bone grafting procedures and dental implant placement. In this study, we investigate the effect of ASA at therapeutic concentrations on the proliferation and osteogenic differentiation of human bone marrow stromal cells (BMSCs). Primary cultures of BMSCs were isolated and expanded. Their proliferation in response to ASA 50, 100 and 200 Jlg/ml was evaluated by MTT assay and 3H-thymidine incorporation. Cell cycle machinery was also investigated by FACS and analysis of inhibitors of cyclin-dependent kinases (CDKIs). ASA inhibited BMSC proliferation and DNA synthesis in a dose-dependent manner down to 60% of control (ASA 200 ug/ml) at 72 h. Cell cycle analysis showed a decrease ofBMSCs in the Sand G2/M phases with a concomitant accumulation in GO/ 1 in ASA treated cells. The finding was associated to increased levels of some CDKIs, namely p27 Kipl and p21 Cipl, whereas ASA did not affected p16Ink4A level at any ofthe concentrations employed. The matrix mineralization, that represents the major feature of the osteogenic commitment, was assessed by a specific staining procedure (von Kossa) and by calcium content determlnation.Both the methods demonstrated an extensive reduction (>90%) of extracellular calcification at 200 Jlg/ml ASA. On the basis of our results, we can hypothesize that the widely reported inhibition of bone healing by ASA might be sustained both by a direct anti-proliferative effect on BMSCs and by an alteration ofthe extracellular calcification.Aspirin (acetylsalicylic acid, ASA) represents one of the most widely prescribed drugs worldwide, and is the forefather of the entire class of non-steroidal anti-inflammatory drugs (NSAIDs). Originally employed exclusively for relieving pain, fever and inflammation, ASA further expanded its indications to the treatment of the chronic musculoskeletal conditions and the primary/secondary prophylaxis of stroke and myocardial infarction (1-2).A number of studies have shown that NSAIDs

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p21 Gene Expression Is Modulated by Egr1

Cited by 81 publications

References 67 publications

The p53 regulatory geneMDM2is a direct transcriptional target of MYCN in neuroblastoma

The p53 regulatory geneMDM2is a direct transcriptional target of MYCN in neuroblastoma

Resveratrol as a Chemopreventive Agent: A Promising Molecule for Fighting Cancer

Acetylsalicylic Acid Inhibits Proliferation of Human Bone Marrow Stromal Cells and Matrix Mineralization

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