Loss of protein phosphatase 6 in mouse keratinocytes increases susceptibility to ultraviolet-B-induced carcinogenesis

Kato, Hiroyuki; Kurosawa, Koreyuki; Inoue, Yui; Tanuma, Nobuhiro; Momoi, Yuki; Hayashi, Kenjiro; Ogoh, Honami; Nomura, Miyuki; Sakayori, Masato; Kakugawa, Yoichiro; Yamashita, Yoshihisa; Miura, Koh; Maemondo, Makoto; Katakura, Ryuichi; Ito, Shigemi; Sato, Masami; Sato, Iwao; Chiba, Natsuko; Watanabe, Toshio; Shima, Hiroshi

doi:10.1016/j.canlet.2015.05.022

Cited by 21 publications

(29 citation statements)

References 31 publications

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“…Comparison of PP6 complex expression in cultured human cell lines showed the highest levels in breast cancer (MCF7), prostate cancer (PC‐3), cervical cancer (HeLa) cells relative to fibroblast HS‐68, and retinal epithelial ARPE19 cells (Stefansson and Brautigan, ). PP6 complex functions as a significant regulator of a number of cellular processes, including chromosome stability (Hammond et al, ), DNA damage response (Mi et al, ; Douglas et al, ; Zhong et al, ; Kato et al, ), cell cycle progression (Stefansson and Brautigan ) and pre‐mRNA splicing (Kamoun et al, ). The detected fusion gene consisted of the promoter region of PPP6R3 fused to the entire coding region of USP6 , indicating a promoter‐swapping mechanism.…”

Section: Discussionmentioning

confidence: 99%

PPP6R3‐USP6 amplification: Novel oncogenic mechanism in malignant nodular fasciitis

Guo

Wang

Chou

et al. 2016

Genes Chromosomes & Cancer

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Nodular fasciitis (NF) is a clonal self-limited neoplastic proliferation characterized by rearrangements of the USP6 locus in most examples. To our knowledge well-documented malignant behavior has never been previously observed in NF. In this report we present an unusual case of NF with classical histologic features that showed a protracted clinical course characterized by multiple recurrences and eventual metastatic behavior over a period of 10 years. Molecular analyses revealed the presence and amplification of the novel PPPR6-USP6 gene fusion, which resulted in USP6 mRNA transcriptional upregulation. These findings further support the oncogenic role of the USP6 protease in mesenchymal neoplasia and expand the biologic potential of NF. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

PPP6R3‐USP6 amplification: Novel oncogenic mechanism in malignant nodular fasciitis

Guo

Wang

Chou

et al. 2016

Genes Chromosomes & Cancer

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“…14 In normal skin, a single treatment with 7,12-dimethylbenz(a)anthracene (DMBA) does not produce papillomas in the absence of tumor promoters 16 ; however, we subsequently reported that a single DMBA application was sufficient to generate papillomas in Ppp6cdeficient skin, suggesting that Ppp6c loss predisposes cells to DMBA-induced papilloma formation. 14 Using the same mice, Kato et al 17 reporte that Ppp6c loss in mouse keratinocytes increases susceptibility to UVB-induced carcinogenesis. These latter 2 studies were the first to report that Ppp6c loss-of-function acts as a tumor promoter in mice.…”

Section: Introductionmentioning

confidence: 99%

Loss of protein phosphatase 6 in mouse keratinocytes enhances K‐ras^G12D‐driven tumor promotion

et al. 2018

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Here, we address the function of protein phosphatase 6 (PP6) loss on K‐ras‐initiated tumorigenesis in keratinocytes. To do so, we developed tamoxifen‐inducible double mutant (K‐ras G12D‐expressing and Ppp6c‐deficient) mice in which K‐ras G12D expression is driven by the cytokeratin 14 (K14) promoter. Doubly‐mutant mice showed early onset tumor formation in lips, nipples, external genitalia, anus and palms, and had to be killed by 3 weeks after induction by tamoxifen, while comparably‐treated K‐ras G12D‐expressing mice did not. H&E‐staining of lip tumors before euthanasia revealed that all were papillomas, some containing focal squamous cell carcinomas. Immunohistochemical analysis of lips of doubly‐mutant vs K‐ras G12D mice revealed that cell proliferation and cell size increased approximately 2‐fold relative to K‐ras G12D‐expressing mutants, and epidermal thickness of lip tissue greatly increased relative to that seen in K‐ras G12D‐only mice. Moreover, AKT phosphorylation increased in K‐ras G12D‐expressing/Ppp6c‐deficient cells, as did phosphorylation of the downstream effectors 4EBP1, S6 and GSK3, suggesting that protein synthesis and survival signals are enhanced in lip tissues of doubly‐mutant mice. Finally, increased numbers of K14‐positive cells were present in the suprabasal layer of doubly‐mutant mice, indicating abnormal keratinocyte differentiation, and γH2AX‐positive cells accumulated, indicating perturbed DNA repair. Taken together, Ppp6c deficiency enhances K‐ras G12D‐dependent tumor promotion.

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“…As phosphatases, they all are involved in a diverse set of biological pathways due to their wide range of substrates. Until now, PP6 was implicated in regulation of DNA damage response, cell cycle progression, apoptosis, pre-mRNA splicing, signaling through the mTOR pathway and Hippo pathway, and others [19, 22, 23, 25, 28, 33]. Among these multiple functions, mTOR pathway regulation was first considered as the potential cause of the phenotype in our study.…”

Section: Discussionmentioning

confidence: 82%

“…Depleting PP6c sensitizes cells to induced DNA damage [19, 33]. Thus, we speculated that this susceptibility also exists in our PP6c-deficient oocytes and leads to eventual oocyte elimination.…”

Section: Resultsmentioning

confidence: 99%

“…PP6c is recruited to DSB sites by DNA-PK, and PP6 is also required for efficient activation of DNA-PK, which is essential for non-homologous end joining (NHEJ)-mediated repair of DSBs [18, 42]. A recent study also showed that Ppp6c -deficient mouse keratinocytes exhibit a high frequency of both p53- and γH2AX-positive cells, suggestive of DNA damage, as well as up-regulated expression of p53, PUMA, BAX, and cleaved caspase-3 proteins following UVB irradiation [33]. Our in vivo data show that absence of PP6c also leads to higher levels of γH2AX (Fig 4) and defective DNA repair in oocytes, especially massive oocyte death after induced DNA damage (Figs 5 and 6), suggesting that PP6 has a conserved role in DNA damage response, which is essential for gamete production and fertility maintenance.…”

Section: Discussionmentioning

confidence: 99%

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Protein Phosphatase 6 Protects Prophase I-Arrested Oocytes by Safeguarding Genomic Integrity

Meng

Jiang

et al. 2016

PLoS Genet

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Mammalian oocytes are arrested at prophase of the first meiotic division in the primordial follicle pool for months, even years, after birth depending on species, and only a limited number of oocytes resume meiosis, complete maturation, and ovulate with each reproductive cycle. We recently reported that protein phosphatase 6 (PP6), a member of the PP2A-like subfamily, which accounts for cellular serine/threonine phosphatase activity, functions in completing the second meiosis. Here, we generated mutant mice with a specific deletion of Ppp6c in oocytes from the primordial follicle stage by crossing Ppp6cF/F mice with Gdf9-Cre mice and found that Ppp6cF/F; GCre+ mice are infertile. Depletion of PP6c caused folliculogenesis defects and germ cell loss independent of the traditional AKT/mTOR pathway, but due to persistent phosphorylation of H2AX (a marker of double strand breaks), increased susceptibility to DNA damage and defective DNA repair, which led to massive oocyte elimination and eventually premature ovarian failure (POF). Our findings uncover an important role for PP6 as an indispensable guardian of genomic integrity of the lengthy prophase I oocyte arrest, maintenance of primordial follicle pool, and thus female fertility.

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Loss of protein phosphatase 6 in mouse keratinocytes increases susceptibility to ultraviolet-B-induced carcinogenesis

Cited by 21 publications

References 31 publications

PPP6R3‐USP6 amplification: Novel oncogenic mechanism in malignant nodular fasciitis

PPP6R3‐USP6 amplification: Novel oncogenic mechanism in malignant nodular fasciitis

Loss of protein phosphatase 6 in mouse keratinocytes enhances K‐ras^G12D‐driven tumor promotion

Protein Phosphatase 6 Protects Prophase I-Arrested Oocytes by Safeguarding Genomic Integrity

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Loss of protein phosphatase 6 in mouse keratinocytes increases susceptibility to ultraviolet-B-induced carcinogenesis

Cited by 21 publications

References 31 publications

PPP6R3‐USP6 amplification: Novel oncogenic mechanism in malignant nodular fasciitis

PPP6R3‐USP6 amplification: Novel oncogenic mechanism in malignant nodular fasciitis

Loss of protein phosphatase 6 in mouse keratinocytes enhances K‐rasG12D‐driven tumor promotion

Protein Phosphatase 6 Protects Prophase I-Arrested Oocytes by Safeguarding Genomic Integrity

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Loss of protein phosphatase 6 in mouse keratinocytes enhances K‐ras^G12D‐driven tumor promotion