Serine/threonine protein phosphatase 6 modulates the radiation sensitivity of glioblastoma

Shen, Yifeng; Wang, Y; Sheng, Kuo Ching; Fei, X; Guo, Qige; Larner, James M.; Kong, Xiangdong; Qiu, Yongming; Mi, Jun

doi:10.1038/cddis.2011.126

Cited by 35 publications

(37 citation statements)

References 30 publications

(44 reference statements)

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“…35 Using a DNA-PK kinase assay and assessing the phosphorylation status of replication protein A 2, a previous study demonstrated IR-induced DNA-PK activity in glioblastoma cell lines. 36 This increased activity was correlated with the survival fraction of those cells after a 5-Gy dose of irradiation, which suggests the role of DNA-PK in radiation resistance. 36 Furthermore, different studies have demonstrated the efficacy of its inhibition in promoting radio-sensitization of glioblastoma by inducing autophagy.…”

Section: Discussionmentioning

confidence: 86%

“…36 This increased activity was correlated with the survival fraction of those cells after a 5-Gy dose of irradiation, which suggests the role of DNA-PK in radiation resistance. 36 Furthermore, different studies have demonstrated the efficacy of its inhibition in promoting radio-sensitization of glioblastoma by inducing autophagy. 37 In conclusion, considering the important impact of MSI1 on DNA repair, radio-resistance, and other cancer-relevant processes, 13 MSI1 targeting can prove to be an important avenue for the treatment of glioblastoma patients when combined with radiotherapy.…”

Section: Discussionmentioning

confidence: 86%

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Musashi1 Impacts Radio-Resistance in Glioblastoma by Controlling DNA-Protein Kinase Catalytic Subunit

Araújo

Gorthi

Silva

et al. 2016

The American Journal of Pathology

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The conserved RNA-binding protein Musashi1 (MSI1) has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation and as a key oncogenic factor in numerous solid tumors, including glioblastoma. To explore the potential use of MSI1 targeting in therapy, we studied MSI1 in the context of radiation sensitivity. Knockdown of MSI1 led to a decrease in cell survival and an increase in DNA damage compared to control in cells treated with ionizing radiation. We subsequently examined mechanisms of double-strand break repair and found that loss of MSI1 reduces the frequency of nonhomologous end-joining. This phenomenon could be attributed to the decreased expression of DNAeprotein kinase catalytic subunit, which we have previously identified as a target of MSI1. Collectively, our results suggest a role for MSI1 in double-strand break repair and that its inhibition may enhance the effect of radiotherapy. Glioblastoma multiforme is the most aggressive form of glioma and is the most common among primary brain tumors. The current standard of care for newly diagnosed glioblastoma is surgical resection, followed by concurrent temozolomide and radiotherapy, then by maintenance chemotherapy with temozolomide. Unfortunately, this route offers a median survival of only approximately 14 months.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 86%

Musashi1 Impacts Radio-Resistance in Glioblastoma by Controlling DNA-Protein Kinase Catalytic Subunit

Araújo

Gorthi

Silva

et al. 2016

The American Journal of Pathology

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“…PP6 regulates the activities of many host proteins (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), and it is therefore possible that PP6 silencing perturbs the virus life cycle by affecting other cellular processes. However, the fact that PP6 interacts directly with the viral RdRP suggests that it plays a direct role in the viral life cycle by regulating the posttranslational modifications of viral proteins.…”

Section: Discussionmentioning

confidence: 99%

“…PP6 is a member of the PP2A subfamily of protein phosphatases, cellular enzymes that catalyze the liberation of inorganic phosphate from proteins and peptides at serine or threonine residues (22). PP6 is a significant regulator of a number of cellular processes, including chromosome stability and the DNA damage response (23)(24)(25)(26)(27), mitosis and the regulation of cell cycle progression (22,(28)(29)(30)(31), signaling (32,33), pre-mRNA splicing (34), and vesicular trafficking (35). The catalytic subunit PPP6C and the regulatory subunits PPP6R1 and PPP6R3 were found to copurify with the viral RdRP.…”

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confidence: 99%

Interactome Analysis of the Influenza A Virus Transcription/Replication Machinery Identifies Protein Phosphatase 6 as a Cellular Factor Required for Efficient Virus Replication

York

Hutchinson

Fodor

2014

J Virol

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The negative-sense RNA genome of influenza A virus is transcribed and replicated by the viral RNA-dependent RNA polymerase (RdRP). The viral RdRP is an important host range determinant, indicating that its function is affected by interactions with cellular factors. However, the identities and the roles of most of these factors remain unknown. Here, we employed affinity purification followed by mass spectrometry to identify cellular proteins that interact with the influenza A virus RdRP in infected human cells. We purified RdRPs using a recombinant influenza virus in which the PB2 subunit of the RdRP is fused to a Strep-tag. When this tagged subunit was purified from infected cells, copurifying proteins included the other RdRP subunits (PB1 and PA) and the viral nucleoprotein and neuraminidase, as well as 171 cellular proteins. Label-free quantitative mass spectrometry revealed that the most abundant of these host proteins were chaperones, cytoskeletal proteins, importins, proteins involved in ubiquitination, kinases and phosphatases, and mitochondrial and ribosomal proteins. Among the phosphatases, we identified three subunits of the cellular serine/threonine protein phosphatase 6 (PP6), including the catalytic subunit PPP6C and regulatory subunits PPP6R1 and PPP6R3. PP6 was found to interact directly with the PB1 and PB2 subunits of the viral RdRP, and small interfering RNA ( Viruses are obligate intracellular parasites that have been compelled by evolutionary processes to encode a minimal number of proteins for the completion of an infectious life cycle, in order to infect naive hosts and to persist in nature. This is exemplified by RNA viruses, the genomes of which are generally smaller than the genomes of DNA viruses, and therefore they greatly rely on the exploitation and subversion of host cellular proteins, structures, and pathways to facilitate virus replication (1). Transcription and replication of the influenza A virus genome are performed by the virally encoded RNA-dependent RNA polymerase (RdRP), a major determinant of species tropism and pathogenicity and a key player in the adaptation of avian influenza A viruses to mammalian hosts. These characteristics of the viral RdRP are thought to be governed by numerous interactions with cellular factors (reviewed in references 2 and 3). It is therefore of great importance to understand the relationship between the viral transcription/replication machinery and host cellular factors in order to understand how the host cell can influence the function of the viral transcription/replication machinery and vice versa. Insight into the molecular biology of these relationships could lead to novel antiviral strategies and has the potential to identify host-specific interactions that would act as a barrier to pandemic emergence.The genome of influenza A virus, like that of other members of the Orthomyxoviridae, is segmented and consists of eight individual viral ribonucleoprotein (vRNP) complexes. Each vRNP contains single-stranded viral RNA (vRNA) that is en...

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“…PP6 consists of a catalytic subunit, PP6c, and regulatory molecules including SAPS1, -2 and -3. PP6 is mainly expressed in lymphoid, cardiac, and neuronal cells (31)(32)(33). SIT4, a yeast homolog of PP6, was identified as a molecule required for the G 1 to S transition of the cell cycle (34).…”

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confidence: 99%

Protein Phosphatase 6 Controls BCR-Induced Apoptosis of WEHI-231 Cells by Regulating Ubiquitination of Bcl-xL

Kajihara

Sakamoto

Tanabe

et al. 2014

The Journal of Immunology

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Crosslinking BCR in the immature B cell line WEHI-231 causes apoptosis. We found that Bcl-xL was degraded by polyubiquitination upon BCR crosslinking and in this study explored the mechanism that controls the degradation of Bcl-xL. Ser62 of Bcl-xL was phosphorylated by JNK to trigger polyubiquitination, and this was opposed by serine/threonine protein phosphatase 6 (PP6) that physically associated with Bcl-xL. We show BCR crosslinking decreased PP6 activity to allow Ser62 phosphorylation of Bcl-xL. CD40 crosslinking rescues BCR-induced apoptosis, and we found PP6 associated with CD40 and PP6 activation in response to CD40. Our data suggest that PP6 activity is regulated to control apoptosis by modulating Ser62 phosphorylation of Bcl-xL, which results in its polyubiquitination and degradation.

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Serine/threonine protein phosphatase 6 modulates the radiation sensitivity of glioblastoma

Cited by 35 publications

References 30 publications

Musashi1 Impacts Radio-Resistance in Glioblastoma by Controlling DNA-Protein Kinase Catalytic Subunit

Musashi1 Impacts Radio-Resistance in Glioblastoma by Controlling DNA-Protein Kinase Catalytic Subunit

Interactome Analysis of the Influenza A Virus Transcription/Replication Machinery Identifies Protein Phosphatase 6 as a Cellular Factor Required for Efficient Virus Replication

Protein Phosphatase 6 Controls BCR-Induced Apoptosis of WEHI-231 Cells by Regulating Ubiquitination of Bcl-xL

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