umu.sePublications
Change search
Refine search result
1 - 6 of 6
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Aripaka, Karthik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Gudey, Shyam Kumar
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zang, Guangxiang
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schmidt, Alexej
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Åhrling, Samaneh Shabani
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Österman, Lennart
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    von Hofsten, Jonas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer2019In: EBioMedicine, E-ISSN 2352-3964, Vol. 45, p. 192-207Article in journal (Refereed)
    Abstract [en]

    Background: Tumour necrosis factor receptor associated factor 6 (TRAF6) promotes inflammation in response to various cytokines. Aberrant Wnt3a signals promotes cancer progression through accumulation of β-Catenin. Here we investigated a potential role for TRAF6 in Wnt signaling.

    Methods: TRAF6 expression was silenced by siRNA in human prostate cancer (PC3U) and human colorectal SW480 cells and by CRISPR/Cas9 in zebrafish. Several biochemical methods and analyses of mutant phenotype in zebrafish were used to analyse the function of TRAF6 in Wnt signaling.

    Findings: Wnt3a-treatment promoted binding of TRAF6 to the Wnt co-receptors LRP5/LRP6 in PC3U and LNCaP cells in vitro. TRAF6 positively regulated mRNA expression of β-Catenin and subsequent activation of Wnt target genes in PC3U cells. Wnt3a-induced invasion of PC3U and SW480 cells were significantly reduced when TRAF6 was silenced by siRNA. Database analysis revealed a correlation between TRAF6 mRNA and Wnt target genes in patients with prostate cancer, and high expression of LRP5, TRAF6 and c-Myc correlated with poor prognosis. By using CRISPR/Cas9 to silence TRAF6 in zebrafish, we confirm TRAF6 as a key molecule in Wnt3a signaling for expression of Wnt target genes.

    Interpretation: We identify TRAF6 as an important component in Wnt3a signaling to promote activation of Wnt target genes, a finding important for understanding mechanisms driving prostate cancer progression.

  • 2.
    Gudey, Shyam Kumar
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sundar, Reshma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mu, Yabing
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wallenius, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zang, Guangxiang
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Heldin, Carl-Henrik
    Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University.
    TRAF6 stimulates the tumor-promoting effects of TGF beta type I receptor through polyubiquitination and activation of Presenilin 12014In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 7, no 307, article id ra2Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-beta (TGF beta) can be both a tumor promoter and suppressor, although the mechanisms behind the protumorigenic switch remain to be fully elucidated. The TGF beta type I receptor (T beta RI) is proteolytically cleaved in the ectodomain region. Cleavage requires the combined activities of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF-alpha-converting enzyme (TACE). The cleavage event occurs selectively in cancer cells and generates an intracellular domain (ICD) of T beta RI, which enters the nucleus to mediate gene transcription. Presenilin 1 (PS1), a gamma-secretase catalytic core component, mediates intramembrane proteolysis of transmembrane receptors, such as Notch. We showed that TGF beta increased both the abundance and activity of PS1. TRAF6 recruited PS1 to the T beta RI complex and promoted lysine-63-linked polyubiquitination of PS1, which activated PS1. Furthermore, PS1 cleaved T beta RI in the transmembrane domain between valine-129 and isoleucine-130, and ICD generation was inhibited when these residues were mutated to alanine. We also showed that, after entering the nucleus, T beta RI-ICD bound to the promoter and increased the transcription of the gene encoding T beta RI. The TRAF6- and PS1-induced intramembrane proteolysis of T beta RI promoted TGF beta-induced invasion of various cancer cells in vitro. Furthermore, when a mouse xenograft model of prostate cancer was treated with the gamma-secretase inhibitor DBZ {(2S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b, d]azepin-7-yl)-propionamide}, generation of T beta RI-ICD was prevented, transcription of the gene encoding the proinvasive transcription factor Snail1 was reduced, and tumor growth was inhibited. These results suggest that gamma-secretase inhibitors may be useful for treating aggressive prostate cancer.

  • 3.
    Mu, Yabing
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Song, Jie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zang, Guangxiang
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gao, Linlin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gahman, Timothy
    Ludwig Institute for Cancer Research, La Jolla.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TGFβ-induced activation of PKCζ confers invasive prostate cancer growthManuscript (preprint) (Other academic)
    Abstract [en]

    One of the hallmarks for aggressivecancer is the capability oftumor cells to become invasive and metastatic. Cancer cells and tumor stromal cells oftenproduce high levels of transforming growth factor b(TGFb) which initiates intracellular signaling pathways in cancer cells in a contextualdependentmanner. Atypical protein kinase C z(PKCz) is a multifunctional protein which maintains cell polarity of normal epithelial cells, while itsaberrantexpression and activation is linked to tumor progression. Tumor necrosisfactor receptor-associated factor6 (TRAF6) is amplified in lung cancer and caninitiate intracellular oncogenic signals. In prostate cancer cellsTRAF6 promotesligand-induced proteolytic cleavage of TGFbtype I receptor(TbRI), and nuclear translocation of its intracellular domain (ICD) to confer invasion of cancer cells. Here we report our novel findingsthat PKCzharboursa TRAF6 consensus binding site and that TRAF6 causes Lys63-linked polyubiquitination of PKCz. TGFb-induced phosphorylationof PKCzis dependent on TRAF6in prostate cancer cells and we have investigated the potential usefulness of twodifferent inhibitors of PKCzas potential novel anti-cancer drugs.

  • 4.
    Mu, Yabing
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zang, Guangxiang
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Engstrom, U.
    Busch, C.
    Landstrom, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TGF beta-induced phosphorylation of Par6 promotes migration and invasion in prostate cancer cells2015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 112, no 7, p. 1223-1231Article in journal (Refereed)
    Abstract [en]

    Background:

    The Par complex - comprising partition-defective 6 (Par6), Par3, and atypical protein kinase C (aPKC) - is crucial for cell polarisation, the loss of which contributes to cancer progression. Transforming growth factor beta (TGF beta)-induced phosphorylation of Par6 on the conserved serine 345 is implicated in epithelial-to-mesenchymal transition (EMT) in breast cancer. Here we investigated the importance of phosphorylated Par6 in prostate cancer.

    Methods:

    We generated a p-Par6(345)-specific antibody and verified its specificity in vitro. Endogenous p-Par6(345) was analysed by immunoblotting in normal human prostate RWPE1 and prostate cancer (PC-3U) cells. Subcellular localisation of p-Par6(345) in migrating TGF beta-treated PC-3U cells was analysed by confocal imaging. Invasion assays of TGF beta-treated PC-3U cells were performed. p-Par6 expression was immunohistochemically analysed in prostate cancer tissues.

    Results:

    TGF beta induced Par6 phosphorylation on Ser345 and its recruitment to the leading edge of the membrane ruffle in migrating PC-3U cells, where it colocalised with aPKC zeta. The p-Par6-aPKC zeta complex is important for cell migration and invasion, as interference with this complex prevented prostate cancer cell invasion. High levels of activated Par6 correlated with aggressive prostate cancer.

    Conclusions: Increased p-Par6Ser(345) levels in aggressive prostate cancer tissues and cells suggest that it could be a useful novel biomarker for predicting prostate cancer progression.

  • 5. Yakymovych, Ihor
    et al.
    Yakymovych, Mariya
    Zang, Guangxiang
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mu, Yabing
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Heldin, Carl-Henrik
    CIN85 modulates TGF beta signaling by promoting the presentation of TGF beta receptors on the cell surface2015In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 210, no 2, p. 319-332Article in journal (Refereed)
    Abstract [en]

    Members of the transforming growth factor beta (TGF beta) family initiate cellular responses by binding to TGF beta receptor type II (Tf3R11) and type I (TpRI) serine/threonine kinases, whereby Srnad2 and Smad3 are phosphorylated and activated, promoting their association with Smadzi. We report here that T beta RI interacts with the SH3 domains of the adaptor protein CIN85 in response to TGF beta stimulation in a TRAF6-dependent manner. Small interfering RNA mediated knockdown of CIN85 resulted in accumulation of T beta RI in intracellular compartments and diminished TGF beta-stimulated Sniad2 phosphorylation. Overexpression of CIN85 instead increased the amount of T beta RI at the cell surface. This effect was inhibited by a dominant-negative mutant of Rab11, suggesting that CIN85 promoted recycling of TGF beta receptors. CIN85 enhanced TGF beta-stimulated Smad2 phosphorylation, transcriptional responses, and cell migration. CIN85 expression correlated with the degree of malignancy of prostate cancers. Collectively, our results reveal that CIN85 promotes recycling of TGF beta receptors and thereby positively regulates TGF beta signaling.

  • 6.
    Zang, Guangxiang
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Mu, Yabing
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Gao, Linlin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    PKC sigma facilitates lymphatic metastatic spread of prostate cancer cells in a mice xenograft model2019In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 38, no 22, p. 4215-4231Article in journal (Refereed)
    Abstract [en]

    Prostate cancer disseminates primarily into the adjacent lymph nodes, which is related to a poor outcome. Atypical protein kinase C ζ (PKCζ) is highly expressed in aggressive prostate cancer and correlates with Gleason score, clinical stage, and poor prognosis. Here, we report the molecular mechanisms of PKCζ in lymphatic metastasis during prostate cancer progression. Using zinc-finger nuclease technology or PKCζ shRNA lentiviral particles, and orthotopic mouse xenografts, we show that PKCζ-knockout or knockdown from aggressive prostate cancer (PC3 and PC3U) cells, decreasesd tumor growth and lymphatic metastasis in vivo. Intriguingly, PKCζ-knockout or knockdown impaired the activation of AKT, ERK, and NF-κB signaling in prostate cancer cells, thereby impairing the expression of lymphangiogenic factors and macrophage recruitment, resulting in aberrant lymphangiogenesis. Moreover, PKCζ regulated the expression of hyaluronan synthase enzymes, which is important for hyaluronan-mediated lymphatic drainage and tumor dissemination. Thus, PKCζ plays a crucial oncogenic role in the lymphatic metastasis of prostate cancer and is predicted to be a novel therapeutic target for prostate cancer.

1 - 6 of 6
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf