PTEN Has Tumor-Promoting Properties in the Setting of Gain-of-Function p53 Mutations

Li, Yunqing; Guessous, Fadila; Kwon, Sherwin; Kumar, Manish; Ibidapo, Opeyemi; Fuller, Lauren; Johnson, Elizabeth; Lal, Bachchu; Hussaini, Isa M.; Bao, Yongde; Laterra, John; Schiff, David; Abounader, Roger

doi:10.1158/0008-5472.can-07-1963

Cited by 88 publications

(70 citation statements)

References 34 publications

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“…Immunoblotting was performed as previously described 55 using antibodies specific for STAT5B (a kind gift from Dr. Barbara Merk, University of Virginia), KRAS, p-MET (T1349), MET, p-EGFR, EGFR, MEF2, GKLF (KLF4), NF-kB, LaminB1 (Santa Cruz Biotechnologies, Santa Cruz, CA, USA), p-PDGFRa, PDGFRa, p27 or CDK6 (Cell Signaling, Danvers, MA, USA). All blots were stripped and re-probed with b-actin (Santa Cruz Biotechnologies) as a loading control.…”

Section: Methodsmentioning

confidence: 99%

“…The cell-cycle status was assessed using propidium iodide flow cytometry as previously described. 55 Briefly, the cells were transfected with pre-miR-134 or pre-miR-con for 72 h. The cells were washed with PBS, harvested, and fixed in 70% (v/v) ethanol. The cells were then treated with 20 mg/ml of DNase-free RNase and stained with propidium iodide.…”

Section: Methodsmentioning

confidence: 99%

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Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma

Zhang

Mueller

et al. 2014

Cell Death Differ

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Receptor tyrosine kinases (RTKs) are co-deregulated in a majority of glioblastoma (GBM), the most common and most deadly brain tumor. We show that the RTKs MET, EGFR, and PDGFR regulate microRNA-134 (miR-134) in GBM. We find that miR-134 is downregulated in human tumors and cancer stem cells and that its expression inversely correlates with the activation of MET, EGFR, and PDGFR. We demonstrate that miR-134 inhibits cancer cell and stem-cell proliferation, survival, and xenograft growth, as well as cancer stem-cell self-renewal and stemness. We identify KRAS and STAT5B as targets of miR-134, and establish molecular and functional links between RTKs, miR-134, KRAS/STAT5B and malignancy in vitro and in vivo. We show that miR-134 induction is required for the anti-tumor effects of RTK inhibitors. We also uncover the molecular pathways through which RTKs regulate miR-134 expression and demonstrate the involvement of MAPK signaling and the KLF4 transcription factor. We therefore identify miR-134 as a novel RTK-regulated tumor-suppressive hub that mediates RTK and RTK-inhibitor effects on GBM malignancy by controlling KRAS and STAT5B. Cell Death and Differentiation (2014) 21, 720-734; doi:10.1038/cdd.2013; published online 17 January 2014 microRNAs (miRNAs) regulate a wide variety of physiological and pathological processes. 1-3 miRNAs modulate protein expression by binding to the 3 0 untranslated region (3 0 UTR) of target mRNA and promoting RNA degradation and/or inhibiting translation. Single miRNAs can regulate multiple molecules, highlighting a powerful mechanism for the regulation of redundant and cross-talking signal transduction pathways. 4 miRNA dysregulation is a common feature of neoplasia and numerous miRNAs have been characterized as oncogenes or tumor suppressors in many cancers including in glioblastoma (GBM). 3,[5][6][7][8][9][10][11] microRNA-134 (miR-134) has been implicated in the regulation of physiological and developmental processes. It was shown to promote mouse embryonic stem-cell differentiation, dendritogenesis, and stage-specific cortical development. 12-17 miR-134 is downregulated by SIRT1 and involved in synaptic plasticity and memory formation. 18 miR-134 expression is regulated by MEF2 in dendritogenesis 14 and GBM. 19 GBM is the most common and most deadly primary malignant brain tumor. 20,21 The Cancer Genome Atlas and other studies have shown that aberrant expression or activation of the receptor tyrosine kinases (RTKs) EGFR, MET, and PDGFR occurs in a majority of GBM and correlates with poor prognosis. 22 Importantly, multiple RTKs are co-activated in the same GBM tumors and tumor cells. 23,24 KRAS, STAT3, and STAT5 are activated by RTKs and mediate their oncogenic effects. [25][26][27][28] The failure of current treatments for GBM is arguably due to the presence in the tumors of GBM stem cells (GSCs) that are resistant to radioand chemo-therapy and capable of maintaining and propagating the tumors. 29-31 EGFR, MET, PDGFR, and miRNAs have been implicated in the regulation of GSC f...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma

Zhang

Mueller

et al. 2014

Cell Death Differ

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“…28 Although not common, paradoxical PTEN-related cellular biology is not completely inexplicable. PTEN was previously shown to be a tumor promoter in the context of gain-of-function p53 mutations, 29 and recently PTEN was shown to positively regulate neuronal insulin signaling and glucose uptake through inhibition of FAK and ERK1/2 signaling requiring PTEN's protein phosphatase activity. 30 PTEN was also shown to promote cellular migration by interacting with β arrestin, which overcame the cell migration-inhibitory properties of the PTEN C2 domain.…”

Section: Discussionmentioning

confidence: 99%

PTEN-mediated ERK1/2 inhibition and paradoxical cellular proliferation following Pnck overexpression

et al. 2014

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“…contained an alteration of both genes, considering that PTEN may have oncogenic properties by enhancing the stability of gain-of-function p53 mutants (31). We conclude that PTEN may play less of a prognostic role than p53 in the development and malignant transformation of STS in Chinese patients.…”

mentioning

confidence: 84%

Mutational analysis of p53 and PTEN in soft tissue sarcoma

2011

Mol Med Report

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Abstract. p53 and PTEN are the two most frequently mutated tumor suppressors in human cancer. However, literature on the effect of the joint inactivation of tumor-suppressor genes in soft tissue sarcoma (STS) is lacking. The purpose of this study was to investigate whether p53 and PTEN mutations play a role in the carcinogenesis of STS, as well as to evaluate their mutual role in STS pathogenesis. We screened mutations of p53 and PTEN in 86 human STSs using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing, respectively. p53 mutations were detected in 25.6% (22 out of 86) of STSs: 6 cases of p53 mutations were detected in 46 cases of specific reciprocal translocations in STSs (13.0%), 16 cases were detected in 40 cases of nonspecific reciprocal translocations in STSs (40.0%); the majority of the mutations were point mutations in exon 6-7. Furthermore, PTEN mutations were observed in 2 out of 86 STSs (2.3%). Two out of 86 cases revealed a 130th codon G>A missense mutation in exon 8 of PTEN which resulted in an Arg change to Gln in the PTEN protein structure; and a 334th codon A>T missense mutation in exon 8 of PTEN, which resulted in an Asn change to Lys in the PTEN protein structure. All subjects were examined for p53 exon 5-9 mutations and for PTEN exon 5-9 mutations. However, no tumors contained an alteration of the two genes. The findings indicate that p53 mutations may be involved in the oncogenesis of STS and also suggest that p53 may function as a potential molecular marker for distinguishing between STSs with specific reciprocal translocations and nonspecific reciprocal translocations. Although the existence of PTEN mutations in STS was detected, the PTEN mutation frequency was quite low. We conclude that PTEN may have played a less prognostic role than p53 in the development and malignant transformation of STS in the patients examined. IntroductionSomatic mutations of tumor-suppressor genes and oncogenes are the most common genetic alterations found in human malignancies. p53 plays a major role in regulating the response of mammalian cells to stresses and damage, in part, through the transcriptional activation of genes involved in cell cycle control, DNA repair, senescence, angiogenesis and apoptosis (1,2). Deletions or point mutations in p53 are prevalent in the majority of types of human cancer (3,4). Furthermore, mutations in p53 have also been identified as the most common genetic alterations in soft tissue sarcoma (STS) (5).PTEN, a phosphatase with specificity for lipids and proteins, is involved in basic cellular functions including adhesion, migration, proliferation and cell survival (6). PTEN is a tumor-suppressor gene located on chromosome 10q23.3, and somatic mutations in PTEN are now known to cause tumorigenesis in a number of human tissues (7). Germline mutations of PTEN are associated with inherited Cowden and Bannayan-Riley-Ruvalcuba syndromes, which are characterized by multiple benign tumors and with enhanced risk of breast and thyroid cancers...

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PTEN Has Tumor-Promoting Properties in the Setting of Gain-of-Function p53 Mutations

Cited by 88 publications

References 34 publications

Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma

Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma

PTEN-mediated ERK1/2 inhibition and paradoxical cellular proliferation following Pnck overexpression

Mutational analysis of p53 and PTEN in soft tissue sarcoma

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