CREB Is a Novel Nuclear Target of PTEN Phosphatase

Gu, Tingting; Zhang, Zhong; Wang, Jianli; Guo, Jun; Shen, Wen Hong; Yin, Yuxin

doi:10.1158/0008-5472.can-10-3399

Cited by 119 publications

(94 citation statements)

References 20 publications

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“…The importance of PI3K/Akt and ERK activation in mediating increased proliferation in cells expressing TRPM2-S was confirmed by treatment with PI3K and ERK inhibitors, which abolished the increase in cell proliferation. PTEN deficiency has also been reported to enhance cell proliferation by increasing phosphorylation of cAMP-responsive element-binding protein (CREB), a target of its phosphatase, resulting in activation and CREB-mediated transcription (20).…”

Section: Discussionmentioning

confidence: 99%

Role of TRPM2 in cell proliferation and susceptibility to oxidative stress

Chen

Zhang

Tong

et al. 2013

American Journal of Physiology-Cell Physiology

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The transient receptor potential (TRP) channel TRPM2 is an ion channel that modulates cell survival. We report here that full-length (TRPM2-L) and short (TRPM2-S) isoform expression was significantly increased in human neuroblastoma compared with adrenal gland. To differentiate the roles of TRPM2-L and TRPM2-S in cell proliferation and survival, we established neuroblastoma SH-SY5Y cell lines stably expressing either TRPM2 isoform or empty vector. Cells expressing TRPM2-S showed significantly enhanced proliferation, downregulation of phosphatase and tensin homolog (PTEN), and increased protein kinase B (Akt) phosphorylation and cell surface glucose transporter 1 (Glut1) compared with cells expressing TRPM2-L or empty vector. ERK phosphorylation was increased, and forkhead box O 3a (FOXO3a) levels were decreased. Inhibitor studies demonstrated that enhanced proliferation was dependent on phosphatidylinositol 3-kinase/Akt, ERK, and NADPH oxidase activation. On the other hand, TRPM2-S-expressing cells were significantly more susceptible to cell death induced by low H2O2 concentrations (50-100 μM), whereas TRPM2-L-expressing cells were protected. This was associated with a significant increase in FOXO3a, MnSOD (SOD2), and membrane Glut1 in TRPM2-L-expressing cells compared with TRPM2-S expressing cells. We conclude that TRPM2 channels occupy a key role in cell proliferation and survival following oxidative stress in neuroblastoma. Our results suggest that overexpression of TRPM2-S results in increased proliferation through phosphatidylinositol 3-kinase/Akt and ERK pathways, while overexpression of TRPM2-L confers protection against oxidative stress-induced cell death through FOXO3a and SOD. TRPM2 channels may represent a novel future therapeutic target in diseases involving oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Role of TRPM2 in cell proliferation and susceptibility to oxidative stress

Chen

Zhang

Tong

et al. 2013

American Journal of Physiology-Cell Physiology

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“…cAMP response element-binding protein (CREB), a cellular transcription factor, has been shown to be a nuclear substrate of PTEN in vivo and in vitro. 21 Its phosphorylation could be enhanced independently of PI3K/AKT signaling when PTEN is deleted. PTEN could regulate gene transcription and cell growth in a CREB-mediated manner.…”

Section: Pten and Tumor Suppressionmentioning

confidence: 99%

“…PTEN could regulate gene transcription and cell growth in a CREB-mediated manner. 21 Despite the de-phosphorylation functions of PTEN, PTEN can bind proteins through different domains and can function in a phosphatase-independent manner. Shen et al 22 found that nuclear PTEN can bind with centromeric protein C, an integral component of the kinetochore, through its C-tail domain and thus participate in guarding chromosomal integrity.…”

Section: Pten and Tumor Suppressionmentioning

confidence: 99%

The functions of tumor suppressor PTEN in innate and adaptive immunity

Chen

Guo

2017

Cell Mol Immunol

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The tumor suppressor phosphatase and tensin homolog (PTEN) is a lipid and protein phosphatase that is able to antagonize the PI3K/AKT pathway and inhibit tumor growth. PTEN also possesses phosphatase-independent functions. Genetic alterations of PTEN may lead to the deregulation of cell proliferation, survival, differentiation, energy metabolism and cellular architecture and mobility. Although the role of PTEN in tumor suppression is extensively documented and well established, the evidence for its roles in immunity did not start to accumulate until recently. In this review, we will focus on the newly discovered functions of PTEN in the regulation of innate and adaptive immunity, including antiviral responses.

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“…5 In addition, PTEN can also act as a protein phosphatase to dephosphorylate protein substrates. 55,56 To distinguish its activities in suppressing the lipid or the protein pathways, 2 PTEN mutants have been commonly used. PTEN C124S lacks both lipid and protein phosphatase activity, 57 whereas PTEN G129E is lipid phosphatase deficient but retains protein phosphatase activity.…”

Section: Pten Inhibits Plk1 In a Phosphatase-dependent Mannermentioning

confidence: 99%

PTEN regulates PLK1 and controls chromosomal stability during cell division

Zhang

Hou

et al. 2016

Cell Cycle

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PTEN functions as a guardian of the genome through multiple mechanisms. We have previously established that PTEN maintains the structural integrity of chromosomes. In this report, we demonstrate a fundamental role of PTEN in controlling chromosome inheritance to prevent gross genomic alterations. Disruption of PTEN or depletion of PTEN protein phosphatase activity causes abnormal chromosome content, manifested by enlarged or polyploid nuclei. We further identify polo-like kinase 1 (PLK1) as a substrate of PTEN phosphatase. PTEN can physically associate with PLK1 and reduce PLK1 phosphorylation in a phosphatase-dependent manner. We show that PTEN deficiency leads to PLK1 phosphorylation and that a phospho-mimicking PLK1 mutant causes polyploidy, imitating functional deficiency of PTEN phosphatase. Inhibition of PLK1 activity or overexpression of a non-phosphorylatable PLK1 mutant reduces the polyploid cell population. These data reveal a new mechanism by which PTEN controls genomic stability during cell division.

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CREB Is a Novel Nuclear Target of PTEN Phosphatase

Cited by 119 publications

References 20 publications

Role of TRPM2 in cell proliferation and susceptibility to oxidative stress

Role of TRPM2 in cell proliferation and susceptibility to oxidative stress

The functions of tumor suppressor PTEN in innate and adaptive immunity

PTEN regulates PLK1 and controls chromosomal stability during cell division

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