PTEN and p53 are required for hypoxia induced expression of maspin in glioblastoma cells

Eitel, Jacob; Bijangi-Vishehsaraei, Khadijeh; Saadatzadeh, M. Reza; Bhavsar, Janak R.; Murphy, Michael P.; Pollok, Karen E.; Mayo, Lindsey D.

doi:10.4161/cc.8.6.7899

Cited by 36 publications

(29 citation statements)

References 27 publications

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“…We have previously shown that p53 is required for the up-regulation of maspin under hypoxic conditions in glioblastoma cell lines (22). The data in Fig.…”

Section: Significancementioning

confidence: 68%

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Src phosphorylation converts Mdm2 from a ubiquitinating to a neddylating E3 ligase

Batuello¹,

Hauck

Gendron³

et al. 2015

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

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Murine double minute-2 protein (Mdm2) is a multifaceted phosphorylated protein that plays a role in regulating numerous proteins including the tumor suppressor protein p53. Mdm2 binds to and is involved in conjugating either ubiquitin or Nedd8 (Neural precursor cell expressed, developmentally down-regulated 8) to p53. Although regulation of the E3 ubiquitin activity of Mdm2 has been investigated, regulation of the neddylating activity of Mdm2 remains to be defined. Here we show that activated c-Src kinase phosphorylates Y281 and Y302 of Mdm2, resulting in an increase in Mdm2 stability and its association with Ubc12, the E2 enzyme of the neddylating complex. Mdm2-dependent Nedd8 conjugation of p53 results in transcriptionally inactive p53, a process that is reversed with a small molecule inhibitor to either Src or Ubc12. Thus, our studies reveal how Mdm2 may neutralize and elevate p53 in actively proliferating cells and also provides a rationale for using therapies that target the Nedd8 pathway in wild-type p53 tumors.

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“…We have previously shown that p53 is required for the up-regulation of maspin under hypoxic conditions in glioblastoma cell lines (22). The data in Fig.…”

Section: Significancementioning

confidence: 68%

“…6), unneddylated p53, and the induction of the downstream target maspin gene. p53 can target many genes including maspin, which can be induced in the absence of extrinsic genotoxic stress (22). Maspin is normally highly expressed in normal breast epithelial cells, but is down-regulated in invasive and metastatic breast carcinoma cells (31).…”

Section: Discussionmentioning

confidence: 99%

Src phosphorylation converts Mdm2 from a ubiquitinating to a neddylating E3 ligase

Batuello¹,

Hauck

Gendron³

et al. 2015

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

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“…33,34 Nuclear PTEN binds to p53 and regulates the expression of hypoxiaresponsive genes and apoptosis. 33,35 In the present study, PTEN is also detected in the nucleus and acts downstream of ROS to induce Bnip3 expression. It would be interesting to know whether ROS induces PTEN nuclear translocation in EBs.…”

Section: Discussionmentioning

confidence: 89%

PTEN induces apoptosis and cavitation via HIF-2-dependent Bnip3 upregulation during epithelial lumen formation

Liu

Saadat

et al. 2014

Cell Death Differ

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The tumor suppressor phosphatase and tensin homolog (PTEN) dephosphorylates PIP3 and antagonizes the prosurvival PI3K-Akt pathway. Targeted deletion of PTEN in mice led to early embryonic lethality. To elucidate its role in embryonic epithelial morphogenesis and the underlying mechanisms, we used embryonic stem cell-derived embryoid body (EB), an epithelial cyst structurally similar to the periimplantation embryo. PTEN is upregulated during EB morphogenesis in parallel with apoptosis of core cells, which mediates EB cavitation. Genetic ablation of PTEN causes Akt overactivation, apoptosis resistance and cavitation blockade. However, rescue experiments using mutant PTEN and pharmacological inhibition of Akt suggest that the phosphatase activity of PTEN and Akt are not involved in apoptosis-mediated cavitation. Instead, hypoxia-induced upregulation of Bnip3, a proapoptotic BH3-only protein, mediates PTEN-dependent apoptosis and cavitation. PTEN inactivation inhibits hypoxia-and reactive oxygen species-induced Bnip3 elevation. Overexpression of Bnip3 in PTEN-null EBs rescues apoptosis of the core cells. Mechanistically, suppression of Bnip3 following PTEN loss is likely due to reduction of hypoxia-inducible factor-2α (HIF-2α) because forced expression of an oxygen-stable HIF-2α mutant rescues Bnip3 expression and apoptosis. Lastly, we show that HIF-2α is upregulated by PTEN at both transcriptional and posttranscriptional levels. Ablation of prolyl hydroxylase domain-containing protein 2 (PHD2) in normal EBs or inhibition of PHD activities in PTEN-null EBs stabilizes HIF-2α and induces Bnip3 and caspase-3 activation. Altogether, these results suggest that PTEN is required for apoptosis-mediated cavitation during epithelial morphogenesis by regulating the expression of HIF-2α and Bnip3.

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“…In contrast, only 2 of 10 cell lines with high pAKT S473 basal levels showed phosphorylation of HER3 Y1289 on Axl inhibition or knockdown ( Figure 3C). The high basal phosphorylation of AKT S473 mainly appears in cell lines with loss of PTEN-or PI3K-activating mutations such as the brain tumor cell lines U373, SF126, and U118 [39,40]. These cell lines are less sensitive to the Axl/ PI3K/AKT signaling pathway inhibition and do not respond through HER3 up-regulation to the inhibition of the upstream RTK Axl.…”

Section: Discussionmentioning

confidence: 99%

801: Activation of HER3 interferes with antitumor effects of Axl receptor tyrosine kinase inhibitors − suggestion of combination therapy

Torka¹,

Pénzes²,

Baumann³

et al. 2014

European Journal of Cancer

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The Axl receptor tyrosine kinase (RTK) has been established as a strong candidate for targeted therapy of cancer. However, the benefits of targeted therapies are limited due to acquired resistance and activation of alternative RTKs. Therefore, we asked if cancer cells are able to overcome targeted Axl therapies. Here, we demonstrate that inhibition of Axl by short interfering RNA or the tyrosine kinase inhibitor (TKI) BMS777607 induces the expression of human epidermal growth factor receptor 3 (HER3) and the neuregulin 1(NRG1)-dependent phosphorylation of HER3 in MDA-MB231 and Ovcar8 cells. Moreover, analysis of 20 Axl-expressing cancer cell lines of different tissue origin indicates a low basal phosphorylation of RAC-α serine/threonine-protein kinase (AKT) as a general requirement for HER3 activation on Axl inhibition. Consequently, phosphorylation of AKT arises as an independent biomarker for Axl treatment. Additionally, we introduce phosphorylation of HER3 as an independent pharmacodynamic biomarker for monitoring of anti-Axl therapy response. Inhibition of cell viability by BMS777607 could be rescued by NRG1-dependent activation of HER3, suggesting an escape mechanism by tumor microenvironment. The Axl-TKI MPCD84111 simultaneously blocked Axl and HER2/3 signaling and thereby prohibited HER3 feedback activation. Furthermore, dual inhibition of Axl and HER2/3 using BMS777607 and lapatinib led to a significant inhibition of cell viability in Axl-expressing MDA-MB231 and Ovcar8 cells. Therefore, we conclude that, in patient cohorts with expression of Axl and low basal activity of AKT, a combined inhibition of Axl and HER2/3 kinase would be beneficial to overcome acquired resistance to Axl-targeted therapies.

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PTEN and p53 are required for hypoxia induced expression of maspin in glioblastoma cells

Cited by 36 publications

References 27 publications

Src phosphorylation converts Mdm2 from a ubiquitinating to a neddylating E3 ligase

Src phosphorylation converts Mdm2 from a ubiquitinating to a neddylating E3 ligase

PTEN induces apoptosis and cavitation via HIF-2-dependent Bnip3 upregulation during epithelial lumen formation

801: Activation of HER3 interferes with antitumor effects of Axl receptor tyrosine kinase inhibitors − suggestion of combination therapy

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