Deacetylation of p53 after nerve growth factor treatment in PC12 cells as a post-translational modification mechanism of neurotrophin-induced tumor suppressor activation

Vaghefi, Houman; Neet, Kenneth E.

doi:10.1038/sj.onc.1207953

Cited by 24 publications

(20 citation statements)

References 80 publications

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“…Vaghefi et al (38) revealed that deacetylation of p53 was a nerve growth factor (NGF)-dependent post-translational mechanism of p53 activation. Additionally, Richardson et al (39) reported that NGF had increased expression in the painful degenerate intervertebral disc.…”

Section: Discussionmentioning

confidence: 99%

Identification of the potential molecular targets for human intervertebral disc degeneration based on bioinformatic methods

Xue

Liu

et al. 2015

International Journal of Molecular Medicine

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Abstract. The present study aimed to explore potential molecular targets and gain further insights into the mechanism of intervertebral disc degeneration (IDD) progression. Microarray datasets of GSE19943, GSE15227 and GSE34095 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) in 3 IDD specimens compared with 3 controls in GSE34095, DEGs in 7 grade III and 3 grade IV samples compared with 5 grade II samples in GSE19943, and differentially expressed miRNAs in 3 degenerated samples compared with 3 controls in GSE15227 were screened. Grade III-and IV-specific networks were constructed and grade-specific genes were extracted. The network features were analyzed, followed by Gene Ontology (GO) enrichment analysis and pathway enrichment analysis of grade-specific genes and DEGs identified in GSE34095. Furthermore, miRNA-pathway interactions were analyzed using Fisher's exact test. Tumor protein p53 (TP53) was a hub gene in the grade III-specific network and ubiquitin C (UBC) was identified to be a hub gene in the grade IV-specific network. Six significant features were identified by grade-specific network topology analysis. Grade-specific genes and DEGs were involved in different GO terms and pathways. Differentially expressed miRNAs were identified to participate in 35 pathways, among which 6 pathways were significantly enriched by DEGs, including apoptosis. The present study identified that key genes (TP53 and UBC) and miR-129-5p may participate in the mechanism of IDD progression. Thus, they may be potential therapeutic targets for IDD.

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Section: Discussionmentioning

confidence: 99%

Identification of the potential molecular targets for human intervertebral disc degeneration based on bioinformatic methods

Xue

Liu

et al. 2015

International Journal of Molecular Medicine

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“…Parc interacts with and sequesters p53 in the cytoplasm and, therefore, prevents its translocation to the nucleus (46). Histone deacetylase 1 (HDAC-1) down-regulates p53-dependent gene activation by reducing the acetylation level of p53, whereas nerve growth factor promotes the p53 deacetylation by increasing HDAC-1 activity (47,48). SV 40 large antigen and Plk1 interact with the DNA binding domain and attenuate the binding of p53 to promoter, thus repressing p53 transcriptional activity (49,50).…”

Section: Discussionmentioning

confidence: 99%

DJ-1 Decreases Bax Expression through Repressing p53 Transcriptional Activity

Fan

Ren

Jia

et al. 2008

Journal of Biological Chemistry

211

187

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DJ-1, originally identified as an oncogene product, is a protein with various functions in cellular transformation, oxidative stress response, and transcriptional regulation. Although previous studies suggest that DJ-1 is cytoprotective, the mechanism by which DJ-1 exerts its survival functions remains largely unknown. Here we show that DJ-1 exerts its cytoprotection through inhibiting p53-Bax-caspase pathway. DJ-1 interacts with p53 in vitro and in vivo. Overexpression of DJ-1 decreases the expression of Bax and inhibits caspase activation, whereas knockdown of DJ-1 increases Bax protein levels and accelerates caspase-3 activation and cell death induced by UV exposure. Our data provide evidence that the protective effects of DJ-1 on apoptosis are associated with its ability of decreasing Bax level through inhibiting p53 transcriptional activity.

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“…The potential mechanisms whereby p53 levels increase in TrkA-expressing NB cells remain to be identified, and they include HDM2-induced ubiquitination or neddylation, or TAF-1-stimulated phosphorylation of p53 (53,54). In addition, TrkA may signal to p53 in other ways, because it can bind both p53 and c-Abl, a p53 activator (55)(56)(57), and promote the deacetylation of p53 in PC12 cells (58). It is likely that the modulation of p53 and Bcl-2 levels by TrkA occurs at the post-transcriptional level, because several recent cDNA expression profiling studies on NB tumors or SH-SY5Y NB cells stably transfected with TrkA did not report changes in p53 or Bcl-2 genes expression (59,60).…”

Section: Discussionmentioning

confidence: 99%

TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism*[boxs]

Lavoie

LeSauteur

Kohn

et al. 2005

Journal of Biological Chemistry

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Neuroblastoma (NB) is the most frequent solid extracranial tumor in children. Its clinical prognosis correlates with the expression of members of the Trk neurotrophin receptor family, which includes TrkA and TrkB. TrkA expression is associated with favorable prognosis, whereas TrkB expression is associated with poor prognosis. Here we show that TrkA expression induces the apoptosis of NB cells and does so by modulating the levels or activities of a number of proteins involved in regulating cell survival and apoptosis, including p53, Bcl-2, and caspase-3. TrkA increased the expression of p53 target proteins and failed to induce apoptosis in cells where p53 was inactivated by mutation or via expression of dominant inhibitory p53 or E1B55K, indicating that TrkA mediates apoptosis, at least in part, through p53. Treatment with a caspase inhibitor or overexpression of Bcl-X L also prevented TrkA from inducing apoptosis. In contrast, elevated expression of TrkA in non-transformed sympathetic neurons resulted in the suppression of p53 levels and enhanced survival. These results identify apoptosis as a novel biological response of TrkA in NB cells and imply that TrkA is a good prognosis marker for NB due in part to its ability to mediate apoptosis when expressed at sufficient levels. Neuroblastoma (NB)1 is the most common solid extracranial solid tumor of childhood and likely arises from sympathoadrenal precursor cells. The median age at diagnosis is ϳ18 months, and spontaneous tumor regression is frequently observed in patients diagnosed at 1 year of age or younger. In contrast, children older than 1 year diagnosed with NB often experience aggressive tumors that are disseminated, resistant to chemotherapy, and metastasized to bone, and often fatal. An important correlative characteristic of NB is the expression of two of the neurotrophin receptors, the TrkA/nerve growth factor (NGF) receptor and the TrkB/brain-derived neurotrophic factor receptor (1-4). The expression of TrkB, a poor prognosis marker, mediates survival, proliferation, and chemotherapeutic drug resistance (5-10), whereas expression of TrkA, a favorable prognosis marker, induces cell growth arrest and differentiation of cultured NB cells (11)(12)(13). This is consistent with TrkA being expressed in tumors that spontaneously regress. Most NB cell lines, which are derived from malignant tumors, lack or have very low levels of TrkA protein expression. Cell lines with low TrkA expression respond to NGF by differentiating into neuronal-like cells (11). Similarly, expression of TrkA by transfection converts NGF non-responsive NB cells into NGF-responsive cells, both in culture and in vivo, with the typical responses being the cessation of cell growth and differentiation into neural and Schwann cells (12). Thus, TrkA converts malignant NB cells into quiescent differentiated cells.An alternative or additional explanation for why TrkA is a good prognosis marker for NB that might contribute to spontaneous tumor regression is that it may induce apoptosis. Paradoxic...

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Deacetylation of p53 after nerve growth factor treatment in PC12 cells as a post-translational modification mechanism of neurotrophin-induced tumor suppressor activation

Cited by 24 publications

References 80 publications

Identification of the potential molecular targets for human intervertebral disc degeneration based on bioinformatic methods

Identification of the potential molecular targets for human intervertebral disc degeneration based on bioinformatic methods

DJ-1 Decreases Bax Expression through Repressing p53 Transcriptional Activity

TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism*[boxs]

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