umu.sePublikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
TRAF6 promotes TGF beta-induced invasion and cell-cycle regulation via Lys63-linked polyubiquitination of Lys178 in TGF beta type I receptor
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
2015 (Engelska)Ingår i: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 14, nr 4, s. 554-565Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Transforming growth factor (TGF) can act either as a tumor promoter or a tumor suppressor in a context-dependent manner. High levels of TGF are found in prostate cancer tissues and correlate with poor patient prognosis. We recently identified a novel TGF-regulated signaling cascade in which TGF type I receptor (TRI) is activated by the E3 ligase TNF-receptor-associated factor 6 (TRAF6) via the Lys63-linked polyubiquitination of TRI. TRAF6 also contributes to activation of TNF--converting enzyme and presenilin-1, resulting in the proteolytic cleavage of TRI and releasing the intracellular domain of TRI, which is translocated to the nucleus to promote tumor invasiveness. In this report, we provide evidence that Lys178 of TRI is polyubiquitinated by TRAF6. Moreover, our data suggest that TRAF6-mediated Lys63-linked ubiquitination of the TRI intracellular domain is a prerequisite for TGF regulation of mRNA for cyclin D1 (CCND1), expression, as well as for the regulation of other genes controlling the cell cycle, differentiation, and invasiveness of prostate cancer cells.

Ort, förlag, år, upplaga, sidor
Taylor & Francis, 2015. Vol. 14, nr 4, s. 554-565
Nyckelord [en]
cell cycle, cyclin D1, EMT, invasion, prostate cancer, Snail1, TRAF6, transforming growth factor beta
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:umu:diva-101605DOI: 10.4161/15384101.2014.990302ISI: 000350137700018PubMedID: 25622187OAI: oai:DiVA.org:umu-101605DiVA, id: diva2:802524
Tillgänglig från: 2015-04-13 Skapad: 2015-04-07 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Ingår i avhandling
1. TRAF6, a key regulator of TGFβ-induced oncogenesis in prostate cancer
Öppna denna publikation i ny flik eller fönster >>TRAF6, a key regulator of TGFβ-induced oncogenesis in prostate cancer
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Prostate cancer is the most common cancer in men, with the incidence rapidly increasing in Europe over the past two decades. Reliable biomarkers for prostate cancer are currently unavailable. Thus, there is an urgent need for improved biomarkers to diagnose prostate cancer at an early stage and to determine the best treatment options. Higher expression of transforming growth factor-β (TGFβ) has been reported in patients with aggressive cancer.

TGFβ is a multifunctional cytokine that acts as a tumor suppressor during early tumor development, and as a tumor promoter at later stages of cancer. TGFβ signals through the canonical Smad or non-Smad cascade via TGFβ type II and type I receptors. The TGFβ signaling cascade is regulated by various post-translational modifications of its key components. The present investigation aimed to identify a potential function of TRAF6 in TGFβ-induced responses in prostate cancer.

The first two articles of this thesis unveil the proteolytic cleavage of TGFβ type I receptor (TβRI), and the biological importance of the liberated TβRI intracellular domain (TβRI-ICD) in the nucleus. We found that tumor necrosis factor receptor-associated factor 6 (TRAF6) polyubiquitinates TβRI, which leads to cleavage of TβRI by tumor necrosis factor alpha converting enzyme (TACE) in a protein kinase C zeta (PKCζ)-dependent manner. Following ectodomain shedding, TβRI undergoes a second cleavage by presenilin 1 (PS1), which liberates TβRI-ICD. TβRI-ICD translocates to the nucleus, where it regulates its own expression as well as expression of the pro-invasive gene Snail1, thereby promoting invasion. We further found that TβRI-ICD associates with Notch intracellular domain (NICD) to drive expression of the pro-invasive gene Snail1, as well as Notch1 ligand Jag1.

The third article provides evidence that TRAF6 promotes Lys63-linked polyubiquitination of TβRI at Lys178 in a TGFβ-dependent manner. TβRI polyubiquitination was found to be a prerequisite for TβRI nuclear translocation, and thus for regulation of the genes involved in cell cycle, differentiation, and invasion of prostate cancer cells.

In the fourth article we investigated the role of the pro-invasive gene Snail1 in TGFβ-induced epithelial-to-mesenchymal transition (EMT) in prostate cancer cells.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2015. s. 55
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1739
Nyckelord
TβRI, TGFβ, TACE, TRAF6, PS1, PKCζ, TβRI-ICD, NICD, Smad, non-Smad, prostate cancer, Snail1, MMP, p300, p21, PAI1, ubiquitination, cleavage, ICD, invasion, HES1, signaling
Nationell ämneskategori
Cell- och molekylärbiologi
Forskningsämne
patologi
Identifikatorer
urn:nbn:se:umu:diva-108014 (URN)978-91-7601-315-1 (ISBN)
Disputation
2015-09-25, Hörsal Betula, Norrlands Universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Forskningsfinansiär
CancerfondenKempestiftelsernaKnut och Alice Wallenbergs Stiftelse
Tillgänglig från: 2015-09-04 Skapad: 2015-09-01 Senast uppdaterad: 2018-06-07Bibliografiskt granskad

Open Access i DiVA

fulltext(1296 kB)264 nedladdningar
Filinformation
Filnamn FULLTEXT01.pdfFilstorlek 1296 kBChecksumma SHA-512
a0eb77df8466be06cd7eab916135fdb1eac0c08b9cec4fd2ae5b52b470facd47d4dd2d948d1532028e66e4de84da39ad5c45fc9c282020fc6994efda0246156f
Typ fulltextMimetyp application/pdf

Övriga länkar

Förlagets fulltextPubMed

Personposter BETA

Sundar, ReshmaGudey, Shyam KumarLandström, Maréne

Sök vidare i DiVA

Av författaren/redaktören
Sundar, ReshmaGudey, Shyam KumarLandström, Maréne
Av organisationen
Patologi
I samma tidskrift
Cell Cycle
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)Cancer och onkologi

Sök vidare utanför DiVA

GoogleGoogle Scholar
Totalt: 264 nedladdningar
Antalet nedladdningar är summan av nedladdningar för alla fulltexter. Det kan inkludera t.ex tidigare versioner som nu inte längre är tillgängliga.

doi
pubmed
urn-nbn

Altmetricpoäng

doi
pubmed
urn-nbn
Totalt: 807 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf