Página 11 dos resultados de 45945 itens digitais encontrados em 0.053 segundos

‣ Mechanistic Control of Carcinoembryonic Antigen-related Cell Adhesion Molecule-1 (CEACAM1) Splice Isoforms by the Heterogeneous Nuclear Ribonuclear Proteins hnRNP L, hnRNP A1, and hnRNP M*

Dery, Kenneth J.; Gaur, Shikha; Gencheva, Marieta; Yen, Yun; Shively, John E.; Gaur, Rajesh K.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) is expressed in a variety of cell types and is implicated in carcinogenesis. Alternative splicing of CEACAM1 pre-mRNA generates two cytoplasmic domain splice variants characterized by the inclusion (L-isoform) or exclusion (S-isoform) of exon 7. Here we show that the alternative splicing of CEACAM1 pre-mRNA is regulated by novel cis elements residing in exon 7. We report the presence of three exon regulatory elements that lead to the inclusion or exclusion of exon 7 CEACAM1 mRNA in ZR75 breast cancer cells. Heterologous splicing reporter assays demonstrated that the maintenance of authentic alternative splicing mechanisms were independent of the CEACAM1 intron sequence context. We show that forced expression of these exon regulatory elements could alter CEACAM1 splicing in HEK-293 cells. Using RNA affinity chromatography, three members of the heterogeneous nuclear ribonucleoprotein family (hnRNP L, hnRNP A1, and hnRNP M) were identified. RNA immunoprecipitation of hnRNP L and hnRNP A1 revealed a binding motif located central and 3′ to exon 7, respectively. Depletion of hnRNP A1 or L by RNAi in HEK-293 cells promoted exon 7 inclusion, whereas overexpression led to exclusion of the variable exon. By contrast...

‣ Musashi1 Cooperates in Abnormal Cell Lineage Protein 28 (Lin28)-mediated Let-7 Family MicroRNA Biogenesis in Early Neural Differentiation*♦

Kawahara, Hironori; Okada, Yohei; Imai, Takao; Iwanami, Akio; Mischel, Paul S.; Okano, Hideyuki
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Musashi1 (Msi1) is an RNA-binding protein that is highly expressed in neural stem/progenitor cells (NS/PCs) as well as in other tissue stem cells. Msi1 binds to the 3′-UTR of its target mRNAs in NS/PCs, prevents their translation, and interferes with NS/PC differentiation. We previously showed that Msi1 competes with eIF4G to bind poly(A)-binding protein and inhibits assembly of the 80 S ribosome. Here we show that Msi1 works in concert with Lin28 to regulate post-transcriptional microRNA (miRNA) biogenesis in the cropping step, which occurs in the nucleus. Lin28 and its binding partner terminal uridylyltransferase 4 (TUT4) are known to maintain embryonic stem cell pluripotency by blocking let-7 miRNA biogenesis at the dicing step. Interestingly, we found that during early neural differentiation of embryonic stem cells, Msi1 enhanced the localization of Lin28 to the nucleus and also inhibited the nuclear cropping step of another let-7 family miRNA, miR98. These results suggest that Msi1 can influence stem cell maintenance and differentiation by controlling the subcellular localization of proteins involved in miRNA biogenesis, as well as by regulating the translation of its target mRNA.

‣ Syntaxin-1A Interacts with Distinct Domains within Nucleotide-binding Folds of Sulfonylurea Receptor 1 to Inhibit β-Cell ATP-sensitive Potassium Channels*

Chang, Nathan; Liang, Tao; Lin, Xianguang; Kang, Youhou; Xie, Huanli; Feng, Zhong-Ping; Gaisano, Herbert Y.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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The ATP-sensitive potassium (KATP) channel regulates pancreatic β-cell function by linking metabolic status to electrical activity. Syntaxin-1A (Syn-1A), a SNARE protein mediating exocytotic fusion, binds and inhibits the KATP channel via the nucleotide-binding folds (NBFs) of its sulfonylurea receptor-1 (SUR1) regulatory subunit. In this study, we elucidated the precise regions within the NBFs required for Syn-1A-mediated KATP inhibition, using in vitro binding assays, whole cell patch clamp and FRET assay. Specifically, NBF1 and NBF2 were each divided into three subregions, Walker A (WA), signature sequence linker, and Walker B (WB), to make GST fusion proteins. In vitro binding assays revealed that Syn-1A associates with WA and WB regions of both NBFs. Patch clamp recordings on INS-1 and primary rat β-cells showed that Syn-1A-mediated channel inhibition was reversed by co-addition of NBF1-WB (not NBF1-WA), NBF2-WA, and NBF2-WB. The findings were corroborated by FRET studies showing that these truncates disrupted Syn-1A interactions with full-length SUR1. To further identify the binding sites, series single-site mutations were made in the Walker motifs of the NBFs. Only NBF1-WA (K719M) or NBF2-WA (K1385M) mutant no longer bound to Syn-1A; K1385M failed to disrupt Syn-1A-mediated inhibition of KATP channels. These data suggest that NBF1-WA (Lys-719) and NBF2-WA (Lys-1385) are critical for Syn-1A-KATP channel interaction. Taken together...

‣ Phosphodiesterase 3A (PDE3A) Deletion Suppresses Proliferation of Cultured Murine Vascular Smooth Muscle Cells (VSMCs) via Inhibition of Mitogen-activated Protein Kinase (MAPK) Signaling and Alterations in Critical Cell Cycle Regulatory Proteins*

Begum, Najma; Hockman, Steven; Manganiello, Vincent C.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Cyclic nucleotide phosphodiesterase 3 (PDE3) is an important regulator of cyclic adenosine monophosphate (cAMP) signaling within the cardiovascular system. In this study, we examined the role of PDE3A and PDE3B isoforms in regulation of growth of cultured vascular smooth muscle cells (VSMCs) and the mechanisms by which they may affect signaling pathways that mediate mitogen-induced VSMC proliferation. Serum- and PDGF-induced DNA synthesis in VSMCs grown from aortas of PDE3A-deficient (3A-KO) mice was markedly less than that in VSMCs from PDE3A wild type (3A-WT) and PDE3B-deficient (3B-KO) mice. The reduced growth response was accompanied by significantly less phosphorylation of extracellular signal-regulated kinase (ERK) in 3A-KO VSMCs, most likely due to a combination of greater site-specific inhibitory phosphorylation of Raf-1Ser-259 by protein kinase A (PKA) and enhanced dephosphorylation of ERKs due to elevated mitogen-activated protein kinase phosphatase 1 (MKP-1). Furthermore, 3A-KO VSMCs, compared with 3A-WT, exhibited higher basal PKA activity and cAMP response element-binding protein (CREB) phosphorylation, higher levels of p53 and p53 phosphorylation, and elevated p21 protein together with lower levels of Cyclin-D1 and retinoblastoma (Rb) protein and Rb phosphorylation. Adenoviral overexpression of inactive CREB partially restored growth effects of serum in 3A-KO VSMCs. In contrast...

‣ N-Formyl Peptide Receptor 3 (FPR3) Departs from the Homologous FPR2/ALX Receptor with Regard to the Major Processes Governing Chemoattractant Receptor Regulation, Expression at the Cell Surface, and Phosphorylation

Rabiet, Marie-Josèphe; Macari, Laurence; Dahlgren, Claes; Boulay, François
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Among human N-formyl peptide chemoattractant receptors, FPR2/ALX and FPR3 share the highest degree of amino acid identity (83%), and trigger similar cell responses upon ligand binding. Although FPR2/ALX is a promiscuous receptor, FPR3 has only one specific high affinity ligand, F2L, and a more restricted tissue/cell distribution. In this study, we showed that FPR2/ALX behaved as the prototypical receptor FPR1. The agonist-dependent phosphorylation used a hierarchical mechanism with a prominent role of Ser329, Thr332, and Thr335. Phosphorylation of FPR2/ALX was essential for its desensitization but the lack of phosphorylation did not result in enhanced or sustained responses. In contrast, resting FPR3 displayed a marked level of phosphorylation, which was only slightly increased upon agonist stimulation. Another noticeable difference between the two receptors was their subcellular distribution in unstimulated cells. Although FPR2/ALX was evenly distributed at the plasma membrane FPR3 was localized in small intracellular vesicles. By swapping domains between FPR2/ALX and FPR3, we uncovered the determinants involved in the basal phosphorylation of FPR3. Experiments aimed at monitoring receptor-bound antibody uptake showed that the intracellular distribution of FPR3 resulted from a constitutive internalization that was independent of C terminus phosphorylation. Unexpectedly...

‣ ATM Protein-dependent Phosphorylation of Rad50 Protein Regulates DNA Repair and Cell Cycle Control*

Gatei, Magtouf; Jakob, Burkhard; Chen, Philip; Kijas, Amanda W.; Becherel, Olivier J.; Gueven, Nuri; Birrell, Geoff; Lee, Ji-Hoon; Paull, Tanya T.; Lerenthal, Yaniv; Fazry, Shazrul; Taucher-Scholz, Gisela; Kalb, Reinhard; Schindler, Detlev; Waltes, Regina
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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The Mre11/Rad50/NBN complex plays a central role in coordinating the cellular response to DNA double-strand breaks. The importance of Rad50 in that response is evident from the recent description of a patient with Rad50 deficiency characterized by chromosomal instability and defective ATM-dependent signaling. We report here that ATM (defective in ataxia-telangiectasia) phosphorylates Rad50 at a single site (Ser-635) that plays an important adaptor role in signaling for cell cycle control and DNA repair. Although a Rad50 phosphosite-specific mutant (S635G) supported normal activation of ATM in Rad50-deficient cells, it was defective in correcting DNA damage-induced signaling through the ATM-dependent substrate SMC1. This mutant also failed to correct radiosensitivity, DNA double-strand break repair, and an S-phase checkpoint defect in Rad50-deficient cells. This was not due to disruption of the Mre11/Rad50/NBN complex revealing for the first time that phosphorylation of Rad50 plays a key regulatory role as an adaptor for specific ATM-dependent downstream signaling through SMC1 for DNA repair and cell cycle checkpoint control in the maintenance of genome integrity.

‣ Role of Cellular Cholesterol Metabolism in Vascular Cell Calcification*

Geng, Yifan; Hsu, Jeffrey J.; Lu, Jinxiu; Ting, Tabitha C.; Miyazaki, Makoto; Demer, Linda L.; Tintut, Yin
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Vascular calcification impairs vessel compliance and increases the risk of cardiovascular events. We found previously that liver X receptor agonists, which regulate intracellular cholesterol homeostasis, augment PKA agonist- or high phosphate-induced osteogenic differentiation of vascular smooth muscle cells. Because cholesterol is an integral component of the matrix vesicles that nucleate calcium mineral, we examined the role of cellular cholesterol metabolism in vascular cell mineralization. The results showed that vascular smooth muscle cells isolated from LDL receptor null (Ldlr−/−) mice, which have impaired cholesterol uptake, had lower levels of intracellular cholesterol and less osteogenic differentiation, as indicated by alkaline phosphatase activity and matrix mineralization, compared with WT cells. PKA activation with forskolin acutely induced genes that promote cholesterol uptake (LDL receptor) and biosynthesis (HMG-CoA reductase). In WT cells, inhibition of cholesterol uptake by lipoprotein-deficient serum attenuated forskolin-induced matrix mineralization, which was partially reversed by the addition of cell-permeable cholesterol. Prolonged activation of both uptake and biosynthesis pathways by cotreatment with a liver X receptor agonist further augmented forskolin-induced matrix mineralization. Inhibition of either cholesterol uptake...

‣ Dentin Matrix Protein 1 (DMP1) Signals via Cell Surface Integrin*

Wu, Hong; Teng, Pang-Ning; Jayaraman, Thottala; Onishi, Shinsuke; Li, Jinhua; Bannon, Leslie; Huang, Hongzhang; Close, John; Sfeir, Charles
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Dentin matrix phosphoprotein 1 (DMP1) is a non-collagenous, acidic extracellular matrix protein expressed chiefly in bone and dentin. We examined the DMP1 ability to engage cell-surface receptors and subsequently activate intracellular signaling pathways. Our data indeed show that the presence of extracellular DMP1 triggers focal adhesion point formation in human mesenchymal stem cells and osteoblast-like cells. We determine that DMP1 acts via interaction with αvβ3 integrin and stimulates phosphorylation of focal adhesion kinase. Further biochemical characterization confirms the activation of downstream effectors of the MAPK pathways, namely ERK and JNK, after DMP1 treatment. This activation is specifically inhibitable and can also be blocked by the addition of anti-αvβ3 integrin antibody. Furthermore, we show that extracellular treatment with DMP1 stimulates the translocation of phosphorylated JNK to the nucleus and a concomitant up-regulation of transcriptional activation by phosphorylated c-Jun. The evidence presented here indicates that DMP1 is specifically involved in signaling via extracellular matrix-cell surface interaction. Combined with the published DMP1-null data (Feng, J. Q., Ward, L. M., Liu, S., Lu, Y., Xie, Y., Yuan...

‣ Involvement of ATP-sensitive Potassium (KATP) Channels in the Loss of Beta-cell Function Induced by Human Islet Amyloid Polypeptide*

Soty, Maud; Visa, Montse; Soriano, Sergi; del Carmen Carmona, María; Nadal, Ángel; Novials, Anna
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Islet amyloid polypeptide (IAPP) is a major component of amyloid deposition in pancreatic islets of patients with type 2 diabetes. It is known that IAPP can inhibit glucose-stimulated insulin secretion; however, the mechanisms of action have not yet been established. In the present work, using a rat pancreatic beta-cell line, INS1E, we have created an in vitro model that stably expressed human IAPP gene (hIAPP cells). These cells showed intracellular oligomers and a strong alteration of glucose-stimulated insulin and IAPP secretion. Taking advantage of this model, we investigated the mechanism by which IAPP altered beta-cell secretory response and contributed to the development of type 2 diabetes. We have measured the intracellular Ca2+ mobilization in response to different secretagogues as well as mitochondrial metabolism. The study of calcium signals in hIAPP cells demonstrated an absence of response to glucose and also to tolbutamide, indicating a defect in ATP-sensitive potassium (KATP) channels. Interestingly, hIAPP showed a greater maximal respiratory capacity than control cells. These data were confirmed by an increased mitochondrial membrane potential in hIAPP cells under glucose stimulation, leading to an elevated reactive oxygen species level as compared with control cells. We concluded that the hIAPP overexpression inhibits insulin and IAPP secretion in response to glucose affecting the activity of KATP channels and that the increased mitochondrial metabolism is a compensatory response to counteract the secretory defect of beta-cells.

‣ Rho Kinase-2 Activation in Human Endothelial Cells Drives Lysophosphatidic Acid-mediated Expression of Cell Adhesion Molecules via NF-κB p65*

Shimada, Hideaki; Rajagopalan, Lakshman E.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Endothelial cells play an important role in the recruitment of immune cells to a disease locus through the induced expression of chemokines and cell adhesion molecules (CAMs). The proinflammatory lysophospholipid, lysophosphatidic acid (LPA), which is elevated in multiple inflammatory diseases, is a potent activator of the RhoA/Rho kinase signaling pathway and has been shown to induce the expression of CAMs in endothelial cells. The present study was undertaken to map signal transduction downstream of LPA and to investigate the contributions of the Rho kinase isoforms ROCK1 and ROCK2 to adhesion molecule expression in human umbilical vein endothelial cells. LPA activated Rho kinase within minutes and subsequently the NF-κB pathway through phosphorylation of the p65 subunit. The lipid also induced the late expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Pharmacologic inhibition of Rho kinase signaling blocked LPA-induced p65 phosphorylation and suppressed ICAM-1 and VCAM-1 expression. Inhibition of the NF-κB pathway had no impact on LPA-induced Rho kinase activation, but inhibited adhesion molecule expression. Small interfering RNA-facilitated knockdown of each isoform identified ROCK2 as the mediator of LPA-driven phosphorylation of NF-κB p65 and of ICAM-1 and VCAM-1 mRNA and protein induction. Taken collectively...

‣ Cell Division Cycle 7 Is a Novel Regulator of Transforming Growth Factor-β-induced Smooth Muscle Cell Differentiation*

Shi, Ning; Xie, Wei-Bing; Chen, Shi-You
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Background: Cell differentiation and proliferation are regulated simultaneously during early development, but the underlying mechanisms remain largely unknown.

‣ The Cell Surface Glycoprotein CUB Domain-containing Protein 1 (CDCP1) Contributes to Epidermal Growth Factor Receptor-mediated Cell Migration*

Dong, Ying; He, Yaowu; de Boer, Leonore; Stack, M. Sharon; Lumley, John W.; Clements, Judith A.; Hooper, John D.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Background: Epidermal growth factor (EGF) activates EGF receptor (EGFR) to promote cell migration and cancer.

‣ Follicle-stimulating Hormone Regulates Pro-apoptotic Protein Bcl-2-interacting Mediator of Cell Death-Extra Long (BimEL)-induced Porcine Granulosa Cell Apoptosis*

Wang, Xian-Long; Wu, Yi; Tan, Lu-Bin; Tian, Zhen; Liu, Jing-Hao; Zhu, De-Sheng; Zeng, Shen-Ming
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Background: In the mammalian ovary, 99% of follicles are removed through follicular atresia caused by granulosa cell apoptosis.

‣ S100P Dissociates Myosin IIA Filaments and Focal Adhesion Sites to Reduce Cell Adhesion and Enhance Cell Migration*

Du, Min; Wang, Guozheng; Ismail, Thamir M.; Gross, Stephane; Fernig, David G.; Barraclough, Roger; Rudland, Philip S.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Background: Certain S100 proteins induce cell migration and metastasis but the molecular mechanism is not clear.

‣ TLT-1s, Alternative Transcripts of Triggering Receptor Expressed on Myeloid Cell-like Transcript-1 (TLT-1), Inhibits the Triggering Receptor Expressed on Myeloid Cell-2 (TREM-2)-mediated Signaling Pathway during Osteoclastogenesis*

Yoon, Soo-Hyun; Lee, Yong Deok; Ha, Jeongim; Lee, Youngkyun; Kim, Hong-Hee
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Background: The triggering receptor expressed on myeloid cell (TREM)-mediated signaling is essential for osteoclastogenesis.

‣ Mixed Lineage Leukemia 5 (MLL5) Protein Regulates Cell Cycle Progression and E2F1-responsive Gene Expression via Association with Host Cell Factor-1 (HCF-1)*

Zhou, Peipei; Wang, Zhilong; Yuan, Xiujie; Zhou, Cuihong; Liu, Lulu; Wan, Xiaoling; Zhang, Feng; Ding, Xiaodan; Wang, Chuangui; Xiong, Sidong; Wang, Zhen; Yuan, Jinduo; Li, Qiang; Zhang, Yan
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Background: MLL5 protein regulates cell cycle progression.

‣ Small Molecule Agonist of Very Late Antigen-4 (VLA-4) Integrin Induces Progenitor Cell Adhesion*

Vanderslice, Peter; Biediger, Ronald J.; Woodside, Darren G.; Brown, Wells S.; Khounlo, Sayadeth; Warier, Navin D.; Gundlach, C. William; Caivano, Amy R.; Bornmann, William G.; Maxwell, David S.; McIntyre, Bradley W.; Willerson, James T.; Dixon, Richard A
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Background: Activation of integrins may improve cell retention rates in stem cell transplantation.

‣ Cell Division Cycle 7 Mediates Transforming Growth Factor-β-induced Smooth Muscle Maturation through Activation of Myocardin Gene Transcription*

Shi, Ning; Chen, Shi-You
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Background: Cell division cycle 7 (Cdc7) plays a role in cell fate determination in the early stage of smooth muscle (SM) differentiation.

‣ MT-LOOP-dependent Localization of Membrane Type I Matrix Metalloproteinase (MT1-MMP) to the Cell Adhesion Complexes Promotes Cancer Cell Invasion*

Woskowicz, Anna M.; Weaver, Sarah A.; Shitomi, Yasuyuki; Ito, Noriko; Itoh, Yoshifumi
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Background: MT1-MMP promotes cancer cell invasion.

‣ Cell-permeable Carboxyl-terminal p27Kip1 Peptide Exhibits Anti-tumor Activity by Inhibiting Pim-1 Kinase*

Morishita, Daisuke; Takami, Miho; Yoshikawa, Seiko; Katayama, Ryohei; Sato, Shigeo; Kukimoto-Niino, Mutsuko; Umehara, Takashi; Shirouzu, Mikako; Sekimizu, Kazuhisa; Yokoyama, Shigeyuki; Fujita, Naoya
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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The incidence and death rate of prostate cancer is increasing rapidly. In addition, the low sensitivity of prostate cancer to chemotherapy makes it difficult to treat this condition. The serine/threonine kinase Pim-1 plays an important role in cell cycle progression and apoptosis inhibition, resulting in prostate tumorigenesis. Therefore, Pim-1 inhibition has been expected to be an attractive target for developing new anti-cancer drugs. However, no small compounds targeting Pim-1 have progressed to clinical use because of their lack of specificity. Here, we have reported a new cell-permeable Pim-1 inhibitory p27Kip1 peptide that could interfere with the binding of Pim-1 to its substrates and act as an anti-cancer drug. The peptide could bind to Pim-1 and inhibit phosphorylation of endogenous p27Kip1 and Bad by Pim-1. Treatment of prostate cancer with the peptide induces G1 arrest and subsequently apoptosis in vitro. However, the peptide showed almost no growth inhibitory or apoptosis-inducing effects in normal cells. The peptide could inhibit tumor growth in in vivo prostate cancer xenograft models. Moreover, the peptide treatment could overcome resistance to taxol, one of the first line chemotherapeutic agents for prostate cancer...