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Naoki Watanabe,
Shinji Mii,
Naoya Asai,
Masato Asai,
Kaoru Niimi,
Kaori Ushida,
Takuya Kato,
Atsushi Enomoto,
Hideshi Ishii,
Masahide Takahashi, Yoshiki Murakumo
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ABSTRACT: REV7 (also known as MAD2L2 and MAD2B) is involved in DNA repair, cell cycle regulation, gene expression and carcinogenesis. In vitro studies show that REV7 interacts with several proteins and regulates their function. It has been reported that human REV7 is highly expressed in the adult testis by northern blot analysis. However, the significance of REV7 in mammalian development has not been elucidated. Here, we present analyses of REV7-deficient (Rev7-/-) mice to clarify the significance of Rev7 in mouse development. In WT mice (Rev7+/+), Rev7 expression was ubiquitously observed in the embryo and confined to germ cells in the testes after birth. Rev7-/- mice exhibited growth retardation and a partial embryonic lethal phenotype. Mice that survived to adulthood were infertile in both sexes and showed germ cell aplasia in the testes and ovaries. Analyses of Rev7-/- embryos revealed that primordial germ cells (PGCs) were present at embryonic day 8.5 (E8.5). However, progressive loss of PGCs was observed during migration, and PGCs were absent in the genital ridges at E13.5. An increase of apoptotic cells was detected not only among PGCs but also in the forebrain of the Rev7-/- embryo, while cell proliferation was unaffected. Moreover, DNA damage accumulation and increased levels of histone methylation were detected in Rev7-/- embryos, and expression of Oct4 and Nanog was deregulated by REV7 deficiency at E8.5. These findings indicate that Rev7 is essential for PGC maintenance by prevention of apoptotic cell death in the mouse.
Journal of Biological Chemistry 03/2013; · 4.77 Impact Factor
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ABSTRACT: Resistance to platinum- and taxane-based chemotherapy is a major cause of treatment failure in ovarian cancer. Thus, it is necessary to develop a predictive marker and molecular target for overcoming drug resistance in ovarian cancer treatment. In a previous report, using an in vitro model, we found that the RET finger protein (RFP) (also known as tripartite motif-containing protein 27, TRIM27) confers cancer cell resistance to anticancer drugs. However, the significance of RFP expression in cancer patients remains elusive. In this study, we showed that RFP was expressed in 62% of ovarian cancer patients and its positivity significantly correlated with drug resistance. Consistent with clinical data, depletion of RFP by RNA interference (RNAi) in ovarian cancer cell lines, SKOV3 and HEY, significantly increased carboplatin- or paclitaxel-induced apoptosis and resulted in reduced anticancer drug resistance. In a nude mouse tumor xenograft model, inoculated RFP-knockdown ovarian cancer cells exhibited lower carboplatin resistance than control cells. These findings suggest that RFP could be a predictive marker for chemoresistance in ovarian cancer patients and also a candidate for a molecular-targeted agent.
Cancer medicine. 10/2012; 1(2):218-29.
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ABSTRACT: Girdin is an Akt substrate and actin-binding protein. Mice with germ-line deletions of Girdin (a non-conditional knockout, (ncKO)) exhibit complete postnatal lethality accompanied by growth retardation and neuronal cell migration defects, which results in hypoplasia of the olfactory bulb and granule cell dispersion in the dentate gyrus. However, the physiological and molecular abnormalities in Girdin ncKO mice are not fully understood. In this study, we first defined the distribution of Girdin in neonates (P1) and adults (6months or older) using β-galactosidase activity in tissues from ncKO mice. The results indicate that Girdin is expressed throughout the nervous system (brain, spinal cord, enteric and autonomic nervous systems). In addition, β-galactosidase activity was detected in non-neural tissues, particularly in tissues with high tensile force, such as tendons, heart valves, and skeletal muscle. In order to identify the cellular population where the Girdin ncKO phenotype originates, newly generated Girdin flox mice were crossed with nestin promoter-driven Cre transgenic mice to obtain Girdin conditional knockout (cKO) mice. The phenotype of Girdin cKO mice was almost identical to ncKO mice, including postnatal lethality, growth retardation and decreased neuronal migration. Our findings indicate that loss of Girdin in the nestin cell lineage underlies the phenotype of Girdin ncKO mice.
Biochemical and Biophysical Research Communications 09/2012; 426(4):533-8. · 2.48 Impact Factor
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Shinji Mii, Yoshiki Murakumo,
Naoya Asai,
Mayumi Jijiwa,
Sumitaka Hagiwara,
Takuya Kato,
Masato Asai,
Atsushi Enomoto,
Kaori Ushida,
Sayaka Sobue,
Masatoshi Ichihara,
Masahide Takahashi
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ABSTRACT: CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is highly expressed in several types of human cancer tissues, in particular, squamous cell carcinomas. In normal human tissues, human CD109 expression is limited to certain cell types including myoepithelial cells of the mammary, lacrimal, salivary, and bronchial glands and basal cells of the prostate and bronchial epithelium. Although CD109 has been reported to negatively regulate transforming growth factor-β signaling in keratinocytes in vitro, its physiologic role in vivo remains largely unknown. To investigate the function of CD109 in vivo, we generated CD109-deficient (CD109(-/-)) mice. Although CD109(-/-) mice were born normally, transient impairment of hair growth was observed. At histologic analysis, kinked hair shafts, ectatic hair follicles with an accumulation of sebum, and persistent hyperplasia of the epidermis and sebaceous glands were observed in CD109(-/-) mice. Immunohistochemical analysis revealed thickening of the basal and suprabasal layers in the epidermis of CD109(-/-) mice, which is where endogenous CD109 is expressed in wild-type mice. Although CD109 was reported to negatively regulate transforming growth factor-β signaling, no significant difference in levels of Smad2 phosphorylation was observed in the epidermis between wild-type and CD109(-/-) mice. Instead, Stat3 phosphorylation levels were significantly elevated in the epidermis of CD109(-/-) mice compared with wild-type mice. These results suggest that CD109 regulates differentiation of keratinocytes via a signaling pathway involving Stat3.
American Journal Of Pathology 07/2012; 181(4):1180-9. · 4.89 Impact Factor
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ABSTRACT: The RET finger protein (RFP) is a transcription factor belonging to the TRIM (tripartite motif) superfamily of proteins. RFP is expressed in a variety of human and rodent tumor cell lines and in several kinds of human cancer. Expression of RFP is associated with prognosis of colon and endometrial cancers. In the present study, we evaluated the expression of RFP in lung cancer and assessed its clinical significance. Tissue microarrays were constructed from 108 cases of lung cancer, and the sections were analyzed for RFP expression by immunohistochemistry. RFP expression was detected in the nucleus in 66.7% of lung cancer tissues examined. RFP expression was statistically significantly associated with thyroid transcription factor 1 (TTF-1) expression (P= 0.028). However, no significant association was observed between RFP expression and other clinicopathological or genetic factors, including epidermal growth factor receptor (EGFR) mutations. Interestingly, we found that RFP expression correlated with poor prognosis in patients with EGFR mutations (P= 0.032). Our results suggest that RFP has a role in mutated EGFR signaling and that RFP status may be a prognostic factor for lung cancer with EGFR mutations.
Pathology International 05/2012; 62(5):324-30. · 1.62 Impact Factor
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Kei Ohara,
Atsushi Enomoto,
Takuya Kato,
Takahiko Hashimoto,
Mayu Isotani-Sakakibara,
Naoya Asai,
Maki Ishida-Takagishi,
Liang Weng,
Masanori Nakayama,
Takashi Watanabe,
Katsuhiro Kato,
Kozo Kaibuchi, Yoshiki Murakumo,
Yoshiki Hirooka,
Hidemi Goto,
Masahide Takahashi
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ABSTRACT: Cell migration is a critical cellular process that determines embryonic development and the progression of human diseases. Therefore, cell- or context-specific mechanisms by which multiple promigratory proteins differentially regulate cell migration must be analyzed in detail. Girdin (girders of actin filaments) (also termed GIV, Gα-interacting vesicle associated protein) is an actin-binding protein that regulates migration of various cells such as endothelial cells, smooth muscle cells, neuroblasts, and cancer cells. Here we show that Girdin regulates the establishment of cell polarity, the deregulation of which may result in the disruption of directional cell migration. We found that Girdin interacts with Par-3, a scaffolding protein that is a component of the Par protein complex that has an established role in determining cell polarity. RNA interference-mediated depletion of Girdin leads to impaired polarization of fibroblasts and mammary epithelial cells in a way similar to that observed in Par-3-depleted cells. Accordingly, the expression of Par-3 mutants unable to interact with Girdin abrogates cell polarization in fibroblasts. Further biochemical analysis suggests that Girdin is present in the Par protein complex that includes Par-3, Par-6, and atypical protein kinase C. Considering previous reports showing the role of Girdin in the directional migration of neuroblasts, network formation of endothelial cells, and cancer invasion, these data may provide a specific mechanism by which Girdin regulates cell movement in biological contexts that require directional cell movement.
PLoS ONE 01/2012; 7(5):e36681. · 4.09 Impact Factor
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Maki Ishida-Takagishi,
Atsushi Enomoto,
Naoya Asai,
Kaori Ushida,
Takashi Watanabe,
Takahiko Hashimoto,
Takuya Kato,
Liang Weng,
Shinji Matsumoto,
Masato Asai, Yoshiki Murakumo,
Kozo Kaibuchi,
Akira Kikuchi,
Masahide Takahashi
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ABSTRACT: Dishevelled is the common mediator of canonical and non-canonical Wnt signalling pathways, which are important for embryonic development, tissue maintenance and cancer progression. In the non-canonical Wnt signalling pathway, the Rho family of small GTPases acting downstream of Dishevelled has essential roles in cell migration. The mechanisms by which the non-canonical Wnt signalling pathway regulates Rac activation remain unknown. Here we show that Daple (Dishevelled-associating protein with a high frequency of leucine residues) regulates Wnt5a-mediated activation of Rac and formation of lamellipodia through interaction with Dishevelled. Daple increases the association of Dishevelled with an isoform of atypical protein kinase C, consequently promoting Rac activation. Accordingly, Daple deficiency impairs migration of fibroblasts and epithelial cells during wound healing in vivo. These findings indicate that Daple interacts with Dishevelled to direct the Dishevelled/protein kinase λ protein complex to activate Rac, which in turn mediates the non-canonical Wnt signalling pathway required for cell migration.
Nature Communications 01/2012; 3:859. · 7.40 Impact Factor
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Yun Wang,
Naoko Kaneko,
Naoya Asai,
Atsushi Enomoto,
Mayu Isotani-Sakakibara,
Takuya Kato,
Masato Asai, Yoshiki Murakumo,
Haruko Ota,
Takao Hikita,
Takashi Namba,
Keisuke Kuroda,
Kozo Kaibuchi,
Guo-li Ming,
Hongjun Song,
Kazunobu Sawamoto,
Masahide Takahashi
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ABSTRACT: In postnatally developing and adult brains, interneurons of the olfactory bulb (OB) are continuously generated at the subventricular zone of the forebrain. The newborn neuroblasts migrate tangentially to the OB through a well defined pathway, the rostral migratory stream (RMS), where the neuroblasts undergo collective migration termed "chain migration." The cell-intrinsic regulatory mechanism of neuroblast chain migration, however, has not been uncovered. Here we show that mice lacking the actin-binding Akt substrate Girdin (a protein that interacts with Disrupted-In-Schizophrenia 1 to regulate neurogenesis in the dentate gyrus) have profound defects in neuroblast chain migration along the RMS. Analysis of two gene knock-in mice harboring Girdin mutants identified unique amino acid residues in Girdin's C-terminal domain that are responsible for the regulation of neuroblast chain migration but revealed no apparent requirement of Girdin phosphorylation by Akt. Electron microscopic analyses demonstrated the involvement of Girdin in neuroblast cell-cell interactions. These findings suggest that Girdin is an important intrinsic factor that specifically governs neuroblast chain migration along the RMS.
Journal of Neuroscience 06/2011; 31(22):8109-22. · 7.11 Impact Factor
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Etsushi Matsushita,
Naoya Asai,
Atsushi Enomoto,
Yoshiyuki Kawamoto,
Takuya Kato,
Shinji Mii,
Kengo Maeda,
Rei Shibata,
Shun Hattori,
Minako Hagikura,
Ken Takahashi,
Masahiro Sokabe, Yoshiki Murakumo,
Toyoaki Murohara,
Masahide Takahashi
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ABSTRACT: Continued exposure of endothelial cells to mechanical/shear stress elicits the unfolded protein response (UPR), which enhances intracellular homeostasis and protect cells against the accumulation of improperly folded proteins. Cells commit to apoptosis when subjected to continuous and high endoplasmic reticulum (ER) stress unless homeostasis is maintained. It is unknown how endothelial cells differentially regulate the UPR. Here we show that a novel Girdin family protein, Gipie (78 kDa glucose-regulated protein [GRP78]-interacting protein induced by ER stress), is expressed in endothelial cells, where it interacts with GRP78, a master regulator of the UPR. Gipie stabilizes the interaction between GRP78 and the ER stress sensor inositol-requiring protein 1 (IRE1) at the ER, leading to the attenuation of IRE1-induced c-Jun N-terminal kinase (JNK) activation. Gipie expression is induced upon ER stress and suppresses the IRE1-JNK pathway and ER stress-induced apoptosis. Furthermore we found that Gipie expression is up-regulated in the neointima of carotid arteries after balloon injury in a rat model that is known to result in the induction of the UPR. Thus our data indicate that Gipie/GRP78 interaction controls the IRE1-JNK signaling pathway. That interaction appears to protect endothelial cells against ER stress-induced apoptosis in pathological contexts such as atherosclerosis and vascular endothelial dysfunction.
Molecular biology of the cell 02/2011; 22(6):736-47. · 5.98 Impact Factor
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ABSTRACT: The glial cell line-derived neurotrophic factor (GDNF)-RET signaling pathway plays an important role in kidney development. We have previously identified a novel zinc finger protein, glial cell line-derived neurotrophic factor-inducible zinc finger protein 1 (GZF1), whose expression was induced in the human neuroblastoma cell line TGW expressing RET by GDNF stimulation and was also detected in mouse metanephric kidney. In the present study, we examined the immunohistochemical expression of GZF1 in normal human kidney and various kidney diseases including chronic kidney disease, acute kidney injury, and cancers, and assessed the clinical significance of GZF1 expression. In the normal kidney, GZF1 was highly expressed only in the proximal tubular epithelial cells that were also positive for angiotensin-converting enzyme. We also evaluated GZF1 expression in various kidney diseases including membranous nephropathy, minimal change nephrotic syndrome with or without acute kidney injury, immunoglobulin A nephropathy, diabetic nephropathy, acute tubular necrosis, and antineutrophil cytoplasmic antibody-related glomerulonephritis. We found that decreased expression of GZF1 was associated with an increase in tubulointerstitial damage and serum creatinine levels. In addition, GZF1 expression was undetectable or very low in most cases of renal cell carcinomas and Wilms tumors. These findings suggest that GZF1 represents a new marker for renal proximal tubules and that there is an inverse correlation between the expression level of GZF1 and tubular function.
Human pathology 02/2011; 42(6):848-58. · 3.03 Impact Factor
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Minako Hagikura, Yoshiki Murakumo,
Masaki Hasegawa,
Mayumi Jijiwa,
Sumitaka Hagiwara,
Shinji Mii,
Shoichi Hagikura,
Yoshihisa Matsukawa,
Yasushi Yoshino,
Ryohei Hattori,
Kenji Wakai,
Shigeo Nakamura,
Momokazu Gotoh,
Masahide Takahashi
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ABSTRACT: Bladder cancer is one of the most common malignant diseases. Since a high-rate of recurrence is a serious problem for early stage urothelial carcinomas, new strategies for the management of recurrent urothelial carcinomas have been explored. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein and is expressed in various cancer tissues, mainly squamous cell carcinomas. CD109 negatively controls transforming growth factor (TGF)-β/Smad signaling in vitro. In this study, we analyzed the clinical significance of CD109 expression in bladder cancer using immunohistochemistry. Of 156 urothelial carcinoma tissues, 69.9% were positive for CD109, whereas CD109 was not expressed in seven normal bladder epithelia. CD109 expression was significantly higher in non-muscle-invasive (pTa+pT1) or low-grade (G1+G2) tumors than in muscle-invasive (pT2-4) or high-grade (G3) tumors, and was associated with cancer-specific survival. Simultaneous immunostaining of CD109 and phosphorylated Smad2 showed an inverse immunoreactivity relationship between the two, suggesting that CD109 inhibits TGF-β/Smad signaling in tumor tissues. Interestingly, CD109 was found to be highly expressed in the basal layer of non-invasive urothelial carcinomas, and the expression pattern was similar to that of CD44, a marker of cancer stem cells. These findings suggest that CD109 is involved in bladder tumorigenesis and is a potential target for cancer immunotherapy.
Pathology International 11/2010; 60(11):735-43. · 1.62 Impact Factor
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Rieko Miyamoto,
Mayumi Jijiwa,
Masato Asai,
Kumi Kawai,
Maki Ishida-Takagishi,
Shinji Mii,
Naoya Asai,
Atsushi Enomoto, Yoshiki Murakumo,
Akihiko Yoshimura,
Masahide Takahashi
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ABSTRACT: The glial cell line-derived neurotrophic factor (GDNF)/RET tyrosine kinase signaling pathway plays crucial roles in the development of the enteric nervous system (ENS) and the kidney. Tyrosine 1062 (Y1062) in RET is an autophosphorylation residue that is responsible for the activation of the PI3K/AKT and RAS/MAPK signaling pathways. Mice lacking signaling via Ret Y1062 show renal hypoplasia and hypoganglionosis of the ENS although the phenotype is milder than the Gdnf- or Ret-deficient mice. Sprouty2 (Spry2) was found to be an antagonist for fibroblast growth factor receptor (FGFR) and acts as an inhibitory regulator of ERK activation. Spry2-deficient mice exhibit hearing loss and enteric nerve hyperplasia. In the present study, we generated Spry2-deficient and Ret Y1062F knock-in (tyrosine 1062 is replaced with phenylalanine) double mutant mice to see if abnormalities of the ENS and kidney, caused by loss of signaling via Ret Y1062, are rescued by a deficiency of Spry2. Double mutant mice showed significant recovery of ureteric bud branching and ENS development in the stomach. These results indicate that Spry2 regulates downstream signaling mediated by GDNF/RET signaling complex in vivo.
Developmental Biology 11/2010; 349(2):160-8. · 4.07 Impact Factor
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Ai Kurotsuchi, Yoshiki Murakumo,
Mayumi Jijiwa,
Kei Kurokawa,
Yasutomo Itoh,
Yoshinori Kodama,
Takuya Kato,
Atsushi Enomoto,
Naoya Asai,
Hiroko Terasaki,
Masahide Takahashi
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ABSTRACT: Point mutations and structural alterations of the RET tyrosine kinase gene cause multiple endocrine neoplasia type 2 (MEN 2) and papillary thyroid carcinoma, respectively. RET activation by glial cell line-derived neurotrophic factor (GDNF) is essential for the development of the enteric nervous system and the kidney. The signal through RET tyrosine kinase requires several adaptor proteins including the DOK (downstream of kinase) family of proteins. Of the seven members of the DOK protein family, DOK-1, -4, -5, and -6 have been reported to play roles in the GDNF-RET signaling pathway. Although DOK-6 has been shown to bind to RET and promote GDNF-induced neurite outgrowth in mouse Neuro2A cells, DOK-6 function in human cells remains unclear. In the present study, we investigated the role of DOK-6 in GDNF-RET signaling in human cells including neuroblastoma cells. DOK-6 was constitutively localized to the plasma membrane via its pleckstrin homology (PH) domain, and was phosphorylated following RET activation via a MEN2A mutation or GDNF stimulation. However, DOK-6 could not significantly affect downstream signaling and neurite outgrowth in human neuroblastoma cells. The binding affinity of the DOK-6 phosphotyrosine-binding (PTB) domain to RET was much lower than that of the DOK-1, DOK-4, and SHC PTB domains to RET. These findings indicate that DOK-6 is involved in RET signaling with less influence when compared with DOK-1, DOK-4, and SHC.
Cancer Science 02/2010; 101(5):1147-55. · 3.33 Impact Factor
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Atsushi Enomoto,
Naoya Asai,
Takashi Namba,
Yun Wang,
Takuya Kato,
Motoki Tanaka,
Hitoshi Tatsumi,
Shinichiro Taya,
Daisuke Tsuboi,
Keisuke Kuroda,
Naoko Kaneko,
Kazunobu Sawamoto,
Rieko Miyamoto,
Mayumi Jijiwa, Yoshiki Murakumo,
Masahiro Sokabe,
Tatsunori Seki,
Kozo Kaibuchi,
Masahide Takahashi
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ABSTRACT: Disrupted-In-Schizophrenia 1 (DISC1), a susceptibility gene for major psychiatric disorders, regulates neuronal migration and differentiation during mammalian brain development. Although roles for DISC1 in postnatal neurogenesis in the dentate gyrus (DG) have recently emerged, it is not known how DISC1 and its interacting proteins govern the migration, positioning, and differentiation of dentate granule cells (DGCs). Here, we report that DISC1 interacts with the actin-binding protein girdin to regulate axonal development. DGCs in girdin-deficient neonatal mice exhibit deficits in axonal sprouting in the cornu ammonis 3 region of the hippocampus. Girdin deficiency, RNA interference-mediated knockdown, and inhibition of the DISC1/girdin interaction lead to overextended migration and mispositioning of the DGCs resulting in profound cytoarchitectural disorganization of the DG. These findings identify girdin as an intrinsic factor in postnatal development of the DG and provide insights into the critical role of the DISC1/girdin interaction in postnatal neurogenesis in the DG.
Neuron 09/2009; 63(6):774-87. · 14.74 Impact Factor
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Hirohisa Tsukamoto,
Takuya Kato,
Atsushi Enomoto,
Nobuhisa Nakamura,
Yohei Shimono,
Mayumi Jijiwa,
Naoya Asai, Yoshiki Murakumo,
Kiyosumi Shibata,
Fumitaka Kikkawa,
Masahide Takahashi
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ABSTRACT: Ret finger protein (RFP) is a nuclear protein with transcriptional repressive activity that is highly expressed in a variety of human and rodent tumor cell lines. We examined the expression of RFP in human endometrial cancer and assessed its clinical significance. Formalin-fixed, paraffin-embedded sections from endometrial cancer tissues were immunostained with the RFP antibody, and the staining intensity was evaluated. The clinicopathological factors examined were age, International Federation of Gynecology and Obstetrics stage, tumor grade, myometrial invasion, and pelvic lymph node metastasis. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. Of the 119 cancer tissues, 57 (47.9%) cases were positive for RFP immunoreactivity. RFP expression was not associated with any of the clinicopathological parameters examined. However, positive RFP expression significantly predicted poorer OS and PFS compared with negative expression (OS, P = 0.0011; PFS, P < 0.0001). In the multivariate analyses, positive RFP expression was an independent prognostic factor for survival in this study. RFP knockdown significantly impaired cancer cell migration and invasion in vitro with concomitant decreases of integrins beta1 and alpha2. Positive RFP expression is a predictive marker for an unfavorable clinical outcome in patients with endometrial cancer.
Cancer Science 08/2009; 100(10):1895-901. · 3.33 Impact Factor
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ABSTRACT: Histone deacetylases (HDAC) are involved in carcinogenesis through their regulation of cell proliferation, differentiation, and survival. The inhibitors of HDAC exhibit profound synergistic effects in cancer treatment when combined with other anticancer drugs. However, the molecular mechanisms underlying this synergy are not fully understood. Here, we show that HDAC1 increases the resistance of cancer cells to oxidative stress by negatively regulating the expression of thioredoxin binding protein 2 (TBP-2). We found that the recruitment of HDAC1 to the TBP-2 promoter is mediated by a protein complex consisting of RET finger protein (RFP; also called TRIM27) and the trimeric transcription factor NF-Y. Accordingly, RNA interference-mediated depletion of RFP led to the disruption of the protein complex and a marked increase in the sensitivity of cancer cells to cisplatin, a potent inducer of oxidative stress. Furthermore, high levels of RFP expression correlated with down-regulation of TBP-2 in human colon cancers and were associated with poor clinical outcome. These findings reveal the diverse cancer-promoting activities of HDAC1 and identify RFP as a key regulator that provides cancer cells with resistance to anticancer drugs.
Cancer Research 05/2009; 69(8):3597-604. · 7.86 Impact Factor
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ABSTRACT: CD109 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein whose expression is up-regulated in squamous cell carcinomas (SCCs) of the lung, esophagus, and uterus. The purpose of this study was to evaluate CD109 expression in oral tumors, including premalignant lesions, and to assess the clinical application of CD109 in oral cancer. CD109 expression in oral normal and tumor tissues from 124 patients was examined by immunohistochemical staining with anti-CD109 antibody, and significant relations between clinical features and CD109 expression were statistically assessed. We found that high levels of CD109 expression were frequently detected in SCCs and premalignant lesions of the oral cavity, but not in normal squamous epithelia. The CD109 expression level was higher in well-differentiated SCCs than in poorly differentiated SCCs. Furthermore, premalignant lesions highly expressing CD109 showed higher risk to progress to SCCs. Oral SCC cell lines overexpressing CD109 exhibited accelerated cell growth in vitro compared with control cell lines. In addition, overexpression of CD109 impaired the transforming growth factor (TGF)-beta1-mediated suppression of cell growth. These findings suggest that CD109 plays a role in the development of oral cancers, and is a useful prognostic marker to predict malignant transformation of premalignant lesions.
Cancer Science 11/2008; 99(10):1916-23. · 3.33 Impact Factor
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Masaki Hasegawa,
Suzuko Moritani, Yoshiki Murakumo,
Tomoko Sato,
Sumitaka Hagiwara,
Chikage Suzuki,
Shinji Mii,
Mayumi Jijiwa,
Atsushi Enomoto,
Naoya Asai,
Shu Ichihara,
Masahide Takahashi
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ABSTRACT: Breast cancer can be classified into several subtypes based on gene expression profiling. Basal-like breast carcinoma (BLC) has a triple negative phenotype, that is, the subtype lacks the estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2). It has been recently reported that CD109, a glycosylphosphatidylinositol (GPI)-anchored cell surface protein, is a new breast myoepithelial marker. In the present study CD109 expression was investigated in invasive ductal carcinomas (IDC) of the breast on immunohistochemistry. Eighty-eight formalin-fixed, paraffin-embedded breast carcinoma sections were immunostained with anti-CD109, anti-cytokeratin 5/6 (CK5/6), anti-calponin, anti-vimentin and anti-p63 antibodies. CD109 expression was detected in 18 of 30 basal-like breast carcinomas (BLC) but not in other types of 53 IDC (non-BLC) that were positive for ER, PgR and/or HER2. The percentage of CD109-positive tissues (60%) in BLC was similar to that of CK5/6 (63%) and higher than that of other myoepithelial markers including p63 (23%), calponin (33%) and vimentin (33%). Statistical analysis indicated that the CD109-positive group in BLC, but not the CK5/6-positive group in BLC, was associated with reduced fat invasion (P < 0.05). These findings indicate that CD109 is a useful diagnostic marker for BLC and that CD109 expression may affect biological properties of cancer cells.
Pathology International 05/2008; 58(5):288-94. · 1.62 Impact Factor
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Mayumi Jijiwa,
Kumi Kawai,
Jun Fukihara,
Akari Nakamura,
Masaki Hasegawa,
Chikage Suzuki,
Tomoko Sato,
Atsushi Enomoto,
Naoya Asai, Yoshiki Murakumo,
Masahide Takahashi
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ABSTRACT: Well-organized spermatogenesis, including the maintenance of spermatogonial stem cells (SSCs), is indispensable for continuous male fertility. Signaling by glial cell line-derived neurotrophic factor (GDNF) via the RET/GDNF family receptor alpha1 (GFRalpha1) receptor complex is essential for self-renewal of murine SSCs and may also regulate their differentiation. When phosphorylated, tyrosine 1062 in RET presents a binding site for the phosphotyrosine-binding domains of several adaptor and effector proteins that are important for activation of a variety of intracellular signaling pathways. In this study, we investigated the role of signaling via RET tyrosine 1062 in spermatogenesis using RET Y1062F knockin mice (Y1062F mice), in which tyrosine 1062 was replaced with phenylalanine. Homozygous Y1062F mice showed marked atrophy of testes due to reduced production of germ cells. RET-expressing spermatogonia in seminiferous tubules of homozygous Y1062F mice decreased after postnatal day (P) 7 and germ cells were almost undetectable by P21. These phenomena appeared to be due to a lack of SSC self-renewal and inability to maintain the undifferentiated state. Our findings suggest that RET signaling via tyrosine 1062 is essential for self-renewal of SSCs and regulation of their differentiation.
Genes to Cells 05/2008; 13(4):365-74. · 2.68 Impact Factor
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ABSTRACT: Girdin (girders of actin filaments) is a novel actin-binding Akt substrate that plays an important role in actin organization and Akt-dependent cell motility in fibroblasts. Here, we find that Girdin is expressed in a variety of cancer cell lines, including the breast cancer cell line MDA-MB-231, and is phosphorylated by the stimulation of insulin-like growth factor (IGF-I). In vitro migration and invasion assays showed that Girdin is required for the IGF-I-dependent cell movement of MDA-MB-231 cells. Short hairpin interfering RNA directed against Girdin markedly inhibited the metastasis of s.c. transplanted MDA-MB-231 cells in nude mice. In addition, Girdin is highly expressed in a variety of human malignant tissues, including breast, colon, lung, and uterine cervical carcinomas. These findings highlight the important role of Girdin in tumor progression in which the Akt signaling pathway is aberrantly activated.
Cancer Research 04/2008; 68(5):1310-8. · 7.86 Impact Factor
