Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous mRNAs

Tay, Yvonne; Kats, Lev; Salmena, Leonardo; Weiss, Dror; Tan, Shen Mynn; Ala, Ugo; Karreth, Florian A.; Poliseno, Laura; Provero, Paolo; Cunto, Ferdinando Di; Lieberman, Judy; Rigoutsos, Isidore; Pandolfi, Pier Paolo

doi:10.1016/j.cell.2011.09.029

Cited by 934 publications

(904 citation statements)

References 38 publications

(46 reference statements)

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“…These differential modulations of target genes results in varying levels of apoptosis or proliferation noticed in these RMS cell lines. As miRNA-mediated regulation of target genes are influenced by various factors such as p53 mutational status 43 and the presence of competing endogenous RNAs, 47 it is possible that presence or absence of these factors may influence the levels of PAX3 or CCND2 in these RMS cells.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma

Sarver

Alamgir

et al. 2012

Laboratory Investigation

105

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Elevated levels of PAX3 and cell proliferation genes are characteristic features of rhabdomyosarcoma (RMS). We hypothesize that the increased levels of these genes are stabilized due to downregulation of specific miRNAs. In this study, we show that downregulation of miR-1, -206 and -29 stabilizes the expression of PAX3 and CCND2 in both embryonal (ERMS) and alveolar (ARMS) RMS types. Ectopic expression of miR-1 and 206 in JR1, an ERMS cell line, show significant downregulation of PAX3 protein expression, whereas overexpression of these miRNAs in Rh30, an ARMS cell line, did not show any effect in PAX3 protein levels. In ARMS, PAX3 forms a fusion transcript with FOXO1 and the resultant loss of PAX3 3 0 UTR in the fusion transcript indicate an oncogenic mechanism to evade miRNA-mediated regulation of PAX3. Further, we show that miR-1, -206 and -29 can regulate the expression of CCND2, a cell cycle gene. In addition to CCND2, miR-29 also targets E2F7, another cell cycle regulator. Cell function analysis shows that overexpression of miR-29 downregulates the expression of these cell cycle genes, induces partial G1 arrest leading to decreased cell proliferation. Taken together our data suggest that the RMS state is stabilized by the deregulation of multiple miRNAs and their target genes, supporting a tumor suppressor role for these miRNA. KEYWORDS: cell cycle genes; miRNAs; PAX3; regulatory networks; rhabdomyosarcoma Rhabdomyosarcoma (RMS) is a malignant striated muscle tumor that accounts for B3% of all childhood cancers. 1 RMS arises from primitive muscle cells and tumors show varying degrees of skeletal muscle differentiation that serves to define their classification as either embryonal (ERMS) or alveolar (ARMS) types. 2,3 ERMS, the most common type has features of embryonic muscle and are generally associated with favorable prognosis. In contrast, ARMS display poor muscle differentiation and are associated with poor outcomes. 4 Most ARMS cases are characterized by chromosomal translocation t(2;13) or t(1;13) involving genes PAX3-FKHR or PAX7-FKHR, respectively. 5 Regulatory disruptions in growth and differentiation pathways of myogenic precursor cells have been implicated in RMS development. Genes involved with muscle cell differentiation and cell proliferation have been associated with RMS development and metastasis. 6-11 Gene expression profiles comparing PAX-FOXO1-positive ARMS vs translocation-negative ERMS have identified genes relevant to tumorigenic process of ARMS and ERMS. 12 microRNAs (miRNAs) have been implicated in RMS. [13][14][15] miRNAs are small (18-22 nucleotides) evolutionarily conserved, non-coding RNAs that post-transcriptionally regulate gene expression through mRNA degradation, translation inhibition or chromatin-based silencing mechanisms. 16 Each miRNA can potentially regulate hundreds of targets either directly or indirectly. miRNAs have been shown to be deregulated in many types of cancers. 17 As a consequence, miRNAs from tumor tissue have been proposed for use in the diagnosis, classif...

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Section: Discussionmentioning

confidence: 99%

Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma

Sarver

Alamgir

et al. 2012

Laboratory Investigation

105

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“…Thus, certain mRNAs possess a coding-independent role in modulating the miRNA activities. [89][90][91][92] The endogenous, miRNA sponge-like transcripts also exist in plants. The first case was discovered in phosphate signaling.…”

Section: Degradome-seqmentioning

confidence: 99%

The use of high-throughput sequencing methods for plant microRNA research

Tang

Qin³

et al. 2015

RNA Biology

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“…PTEN expression is controlled by numerous transcription factors (for example, p53, Egr-1 and CBF-1) and post-transcriptionally via oncogenic microRNAs that target PTEN mRNA 1,2 . Recently, it was shown that both mRNAs of the PTEN pseudogene, PTENP1, and competing endogenous RNAs could serve as decoys for PTEN mRNA-targeting microRNAs, inhibiting their effects on PTEN expression 7,8 . PTEN is also regulated through protein-protein interactions, the association of scaffolding proteins such as MAGI-1 and -2, NHERF and b-arrestins (b-arrs) altering its function and/or subcellular localization [9][10][11][12] .…”

mentioning

confidence: 99%

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

et al. 2014

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Tumour suppressor PTEN is a phosphatase that negatively regulates the PI3K/AKT pathway. The ability to directly monitor PTEN conformation and function in a rapid, sensitive manner is a key step towards developing anti-cancer drugs aimed at enhancing or restoring PTEN-dependent pathways. Here we developed an intramolecular bioluminescence resonance energy transfer (BRET)-based biosensor, capable of detecting signal-dependent PTEN conformational changes in live cells. The biosensor retains intrinsic properties of PTEN, enabling structure-function and kinetic analyses. BRET shifts, indicating conformational change, were detected following mutations that disrupt intramolecular PTEN interactions, promoting plasma membrane targeting and also following physiological PTEN activation. Using the biosensor as a reporter, we uncovered PTEN activation by several G proteincoupled receptors, previously unknown as PTEN regulators. Trastuzumab, used to treat ERBB2-overexpressing breast cancers also elicited activation-associated PTEN conformational rearrangement. We propose the biosensor can be used to identify pathways regulating PTEN or molecules that enhance its anti-tumour activity.

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Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous mRNAs

Cited by 934 publications

References 38 publications

Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma

Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma

The use of high-throughput sequencing methods for plant microRNA research

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

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