Suprachiasmatic Nucleus Circadian Oscillatory Protein, a Novel Binding Partner of K-Ras in the Membrane Rafts, Negatively Regulates MAPK Pathway

Shimizu, Kimiko; Okada, Masato; Nonomura, Katsuya; Fukada, Yoshitaka

doi:10.1074/jbc.m213214200

Cited by 85 publications

(87 citation statements)

References 39 publications

(48 reference statements)

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“…PHLPP1 and PHPPL2 are considered to be tumor suppressors because they suppress cell survival, both by inhibiting proliferative pathways and by promoting apoptotic pathways (23). PHLPP in membrane rafts of rat brains can negatively regulate the proliferative RAS-mitogen-activated protein kinase (MAPK) pathway (39). Furthermore, human PHLPP1 and PHLPP2 can differentially regulate proliferative AKT signaling by selectively dephosphorylating the hydrophobic motifs of AKT2 or AKT3.…”

Section: Discussionmentioning

confidence: 99%

Comparative microRNA Profiling of Prostate Carcinomas with Increasing Tumor Stage by Deep Sequencing

Hart

Nolte

Wach

et al. 2014

Molecular Cancer Research

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MicroRNAs (miRNA) posttranscriptionally regulate gene expression and are important in tumorigenesis. Previous deep sequencing identified the miRNA profile of prostate carcinoma versus nonmalignant prostate tissue. Here, we generated miRNA expression profiles of prostate carcinoma by deep sequencing, with increasing tumor stage relative to corresponding nonmalignant and healthy prostate tissue, and detected clearly changed miRNA expression patterns. The miRNA profiles of the healthy and nonmalignant tissues were consistent with our previous findings, indicating a high fidelity of the method employed. In the tumors, quantitative real-time PCR (qRT-PCR) analysis of 40 paired samples of prostate carcinoma versus normal tissue revealed significant upregulation of miR-20a, miR-148a, miR-200b, and miR-375 and downregulation of miR-143 and miR-145. Hereby, miR-375 increased from normal to organ-confined tumors (pT2 pN0), slightly decreased in tumors with extracapsular growth (pT3 pN0), but was then expressed again at higher levels in lymph node metastasizing (pN1) tumors. The sequencing data for miR-375 were confirmed by Northern blotting and qRT-PCR. The regulation for other selected miRNAs could, however, not be confirmed by qRT-PCR in individual tumor stages. MiR-200b, in addition to miR-200c and miR-375 reduced the expression of SEC23A. Interestingly, miR-375, found by sequencing in pT2 upregulated by us and others in tumor versus normal tissue, and miR-15a, found by sequencing in pT2 and pT3 and in the metastasizing tumors, target the phosphatases PHLPP1 and PHLPP2, respectively. PHLPP1 and PHLPP2 dephosphorylate members of the AKT family of signal transducers, thereby inhibiting cell growth. Coexpression of miR-15a and miR-375 resulted in downregulation of PHLPP1/2 and strongly increased prostate carcinoma cell growth.Implications: These genomic data reveal relevant miRNAs in prostate cancer that may have biomarker and therapeutic potential. Mol Cancer Res; 12(2); 250-63. Ó2013 AACR. IntroductionProstate carcinoma is the second most frequently diagnosed malignancy and a leading cause of cancer-related death in men worldwide (1). The underlying mechanisms resulting in invasive growth after dissemination of the primary tumor from the initial site in the prostate are not completely understood. MicroRNAs (miRNAs) are now recognized as contributing factors to the induction, growth, and metastasis

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Section: Discussionmentioning

confidence: 99%

Comparative microRNA Profiling of Prostate Carcinomas with Increasing Tumor Stage by Deep Sequencing

Hart

Nolte

Wach

et al. 2014

Molecular Cancer Research

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“…20 In addition, both PHLPP1 and PHLPP2 have been shown to dephosphorylate PKCa and PKCbII, whereas PHLPP1 has also been implicated in the negative regulation of the Ras/Raf/MEK/ERK pathway. 22,23 Recently, several lines of evidence have suggested that PHLPP1 and PHLPP2 are involved in the pathogenesis of various types of cancer. Reduced or absent expression of PHLPP1 and PHLPP2 has been reported in approximately 80% of primary colorectal cancer specimen.…”

Section: Introductionmentioning

confidence: 99%

Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells

et al. 2010

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The PI3K/Akt pathway is activated in response to various microenvironmental stimuli that regulate the survival and proliferation of chronic lymphocytic leukemia (CLL) B-cells, including triggering of the B-cell receptor (BCR). Although this pathway is frequently targeted in cancer, no significant alterations have yet been identified in CLL. We now show that the phosphatase PH domain leucin-rich repeat protein phosphatase (PHLPP1), a recently identified tumor suppressor and negative regulator of the Akt kinase, is absent or expressed at substantially reduced levels in CLL B-cells. To determine what the consequences of PHLPP1 loss on BCR signaling are, we downregulated or re-expressed PHLPP1 in lymphoma cell lines and primary CLL B-cells, respectively. Downregulation of PHLPP1 increased BCR-induced phosphorylation and activation of the Akt, GSK3 and ERK kinases, whereas re-expression had the opposite effect. Importantly, re-expression of PHLPP1 in primary CLL cells prevented upregulation of Mcl-1 and inhibited the increase in leukemic cell viability induced by sustained BCR engagement. Enforced expression of PHLPP1 also affected the response to other microenvironmental stimuli, particularly in terms of ERK phosphorylation. Collectively, these data show that CLL cells lack an important negative regulator of the Akt and ERK pathways, which could confer them a growth advantage by facilitating the propagation of crucial microenvironment-derived stimuli.

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“…This arrangement allows for the existence of small, organized membrane microdomains called rafts (1)(2)(3)(4)(5) that orchestrate and regulate a number of signaling processes (6)(7)(8)(9)(10)(11)(12)(13). In order to elucidate mechanisms involved in these processes, it is crucial to understand raft biology.…”

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confidence: 99%

Isolation of rafts from mouse brain tissue by a detergent-free method

Persaud-Sawin

Lightcap

Harry

2009

Journal of Lipid Research

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Membrane rafts are rich in cholesterol and sphingolipids and have specific proteins associated with them. Due to their small size, their identification and isolation have proved to be problematic. Their insolubility in nonionic detergents, such as Triton-X 100, at 4°C has been the most common means of isolation. However, detergent presence can produce artifacts or interfere with ganglioside distribution. The direction is therefore toward the use of detergent-free protocols. We report an optimized method of raft isolation from lipid-rich brain tissue using a detergentfree method. We compared this to Triton-X 100-based isolation along sucrose or Optiprep™ gradients using the following endpoints: low protein content, high cholesterol content, presence of Flotillin 1 (Flot1), and absence of transferrin receptor (TfR) proteins. These criteria were met in raft fractions isolated in a detergent-free buffer along a sucrose gradient of 5%/35%/42.5%. The use of optiprep gave less consistent results with respect to protein distribution. We demonstrate that clean raft fractions with minimal myelin contamination can be reproducibly obtained in the top three low-density fractions along a sucrose step gradient.-Persaud-Sawin, D-A., S. Lightcap, and G. J. Harry. Isolation of rafts from mouse brain tissue by a detergent-free method.

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Suprachiasmatic Nucleus Circadian Oscillatory Protein, a Novel Binding Partner of K-Ras in the Membrane Rafts, Negatively Regulates MAPK Pathway

Cited by 85 publications

References 39 publications

Comparative microRNA Profiling of Prostate Carcinomas with Increasing Tumor Stage by Deep Sequencing

Comparative microRNA Profiling of Prostate Carcinomas with Increasing Tumor Stage by Deep Sequencing

Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells

Isolation of rafts from mouse brain tissue by a detergent-free method

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