p53 is required for nerve growth factor-mediated differentiation of PC12 cells via regulation of TrkA levels

Zhang, Jin; Yan, Wensheng; Chen, Xinbin

doi:10.1038/sj.cdd.4401972

Cited by 37 publications

(45 citation statements)

References 34 publications

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“…In addition, p21 was not induced by NGF in p53 knockdown PC12 cells due to lack of p53 (Fig. 3A, p21, lanes 3 and 4), consistent with a previous report (55). Together, these data suggest that ⌬Np73␣ is capable of inhibiting NGF-mediated neuronal differentiation independent of p53.…”

Section: Vol 27 2007supporting

confidence: 79%

“…It should be mentioned that a higher dosage of NGF (200 ng/ml instead of 100 ng/ml) was used since p53 knockdown renders PC12 cells less sensitive to NGF (55). As shown in Fig.…”

Section: Vol 27 2007mentioning

confidence: 99%

“…The nucleotides in boldface above represent the siRNA target region. pSuper-Si-p53 vector, which expresses an siRNA targeting the rat p53 coding region, pUHD10-3-HA-p53 vector, which expresses HAtagged murine p53, and the luciferase reporters (the wild-type and mutant TrkA promoters) were described previously (55).…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we and others have reported that p53 plays an important role in NGF-mediated neuronal differentiation in PC12 cells (9,55). Since ⌬Np73 has been found to be dominant negative towards p53 (37), it is important to determine whether ⌬Np73 would inhibit NGFmediated neuronal differentiation in the absence of p53.…”

Section: Vol 27 2007mentioning

confidence: 99%

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ΔNp73 Modulates Nerve Growth Factor-Mediated Neuronal Differentiation through Repression of TrkA

Zhang

Chen

2007

Molecular and Cellular Biology

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p73, a member of the p53 family, expresses two classes of proteins: the full-length TAp73 and the Nterminally truncated ⌬Np73. While TAp73 possesses many p53-like features, ⌬Np73 is dominant negative towards TAp73 and p53 and appears to have distinct functions in tumorigenesis and neuronal development. Given its biological importance, we investigated the role of ⌬Np73 in nerve growth factor (NGF)-mediated neuronal differentiation in PC12 cells. We show that overexpression of ⌬Np73␣ or ⌬Np73␤ inhibits NGFmediated neuronal differentiation in both p53-dependent and -independent manners. In line with this, we showed that the level of endogenous ⌬Np73 is progressively diminished in differentiating PC12 cells upon NGF treatment and knockdown of ⌬Np73 promotes NGF-mediated neuronal differentiation. Interestingly, we found that the ability of ⌬Np73 to suppress NGF-mediated neuronal differentiation is correlated with its ability to regulate the expression of TrkA, the high-affinity NGF receptor. Specifically, we found that ⌬Np73 directly binds to the TrkA promoter and transcriptionally represses TrkA expression, which in turn attenuates the NGF-mediated mitogen-activated protein kinase pathway. Conversely, the steady-state level of TrkA is increased upon knockdown of ⌬Np73. Furthermore, we found that histone deacetylase 1 (HDAC1) and HDAC2 are recruited by ⌬Np73 to the TrkA promoter and act as corepressors to suppress TrkA expression, which can be relieved by trichostatin A, an HDAC inhibitor. Taken together, we conclude that ⌬Np73 negatively regulates NGF-mediated neuronal differentiation by transrepressing TrkA.

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Section: Vol 27 2007supporting

confidence: 79%

“…It should be mentioned that a higher dosage of NGF (200 ng/ml instead of 100 ng/ml) was used since p53 knockdown renders PC12 cells less sensitive to NGF (55). As shown in Fig.…”

Section: Vol 27 2007mentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Vol 27 2007mentioning

confidence: 99%

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ΔNp73 Modulates Nerve Growth Factor-Mediated Neuronal Differentiation through Repression of TrkA

Zhang

Chen

2007

Molecular and Cellular Biology

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“…Recent evidence indicates the presence of p53 transcriptional activity in neuronal differentiation and neurite outgrowth in the nervous system [7,8]. In particular, nerve growth factor (NGF) mediated differentiation of rat PC12 pheochromocytoma cells is associated with elevated p53 protein levels, increased p53 transcriptional activity and a rise in p21 Waf1/Cip1 expression which is prevented by temperature sensitive mutant p53 [9].…”

Section: Introductionmentioning

confidence: 99%

Nerve Growth Factor Potentiates p53 DNA Binding but Inhibits Nitric Oxide-Induced Apoptosis in Neuronal PC12 Cells

Brynczka

Merrick

2007

Neurochem Res

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NGF is recognized for its role in neuronal differentiation and maintenance. Differentiation of PC12 cells by NGF involves p53, a transcription factor that controls growth arrest and apoptosis. We investigated NGF influence over p53 activity during NO-induced apoptosis by sodium nitroprusside in differentiated and mitotic PC12 cells. NGF-differentiation produced increased p53 levels, nuclear localization and sequence-specific DNA binding. Apoptosis in mitotic cells also produced these events but the accompanying activation of caspases 1-10 and mitochondrial depolarization were inhibited during NGF differentiation and could be reversed in p53-silenced cells. Transcriptional regulation of PUMA and survivin expression were not inhibited by NGF, although NO-induced mitochondrial depolarization was dependent upon de novo gene transcription and only occurred in mitotic cells. We conclude that NGF mediates prosurvival signaling by increasing factors such as Bcl-2 and p21 Waf1/Cip1 without altering p53 transcriptional activity and prevents mitochondrial depolarization and caspase activation to inhibit apoptosis.

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The A_2A adenosine receptor rescues neuritogenesis impaired by p53 blockage via KIF2A, a kinesin family member

Sun

Chuang

Wang

et al. 2010

Developmental Neurobiology

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The A2A adenosine receptor (A2AR) is a G-protein-coupled receptor. We previously reported that the C terminus of the A2AR binds to translin-associated protein X (TRAX) and modulates nerve growth factor (NGF)-evoked neurite outgrowth in PC12 cells. Herein, we show that neuritogenesis of primary hippocampal neurons requires p53 because blockage of p53 suppressed neurite outgrowth. The impaired neuritogenesis caused by p53 blockage was rescued by activation of the A2AR (designated the A2A rescue effect) in a TRAX-dependent manner. Importantly, suppression of a TRAX-interacting protein (kinesin heavy chain member 2A, KIF2A) inhibited the A2A rescue effect, whereas overexpression of KIF2A caused a rescue effect. Expression of a KIF2A fragment (KIF2A514), which disturbed the interaction between KIF2A and TRAX, blocked the rescue effect. Transient colocalization of TRAX and KIF2A was detected in the nucleus of PC12 cells upon NGF treatment. These data suggest that functional interaction between KIF2A and TRAX is critical for the A2A rescue effect. Moreover, p53 blockage during NGF treatment prevented the redistribution of KIF2A from the nucleus to the cytoplasmic region. Expression of a nuclear-retained KIF2A variant (NLS-KIF2A) did not rescue the impaired neurite outgrowth as did the wild-type KIF2A. Therefore, redistribution of KIF2A to the cytoplasmic fraction is a prerequisite for neurite outgrowth. Collectively, we demonstrate that KIF2A functions downstream of p53 to mediate neuritogenesis of primary hippocampal neurons and PC12 cells. Stimulation of the A2AR rescued neuritogenesis impaired by p53 blockage via an interaction between TRAX and KIF2A.

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p53 is required for nerve growth factor-mediated differentiation of PC12 cells via regulation of TrkA levels

Cited by 37 publications

References 34 publications

ΔNp73 Modulates Nerve Growth Factor-Mediated Neuronal Differentiation through Repression of TrkA

ΔNp73 Modulates Nerve Growth Factor-Mediated Neuronal Differentiation through Repression of TrkA

Nerve Growth Factor Potentiates p53 DNA Binding but Inhibits Nitric Oxide-Induced Apoptosis in Neuronal PC12 Cells

The A_2A adenosine receptor rescues neuritogenesis impaired by p53 blockage via KIF2A, a kinesin family member

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p53 is required for nerve growth factor-mediated differentiation of PC12 cells via regulation of TrkA levels

Cited by 37 publications

References 34 publications

ΔNp73 Modulates Nerve Growth Factor-Mediated Neuronal Differentiation through Repression of TrkA

ΔNp73 Modulates Nerve Growth Factor-Mediated Neuronal Differentiation through Repression of TrkA

Nerve Growth Factor Potentiates p53 DNA Binding but Inhibits Nitric Oxide-Induced Apoptosis in Neuronal PC12 Cells

The A2A adenosine receptor rescues neuritogenesis impaired by p53 blockage via KIF2A, a kinesin family member

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The A_2A adenosine receptor rescues neuritogenesis impaired by p53 blockage via KIF2A, a kinesin family member