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TGFβ engages TRAF6 and p38 to regulate c-Jun activity and invasion of prostate cancer cells.
Ludwig Institute for Cancer Research, Uppsala university. (Marene Landström group)
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap. (Marene Landström group)ORCID-id: K-8186-2013
Ludwig Institute for Cancer Research, Uppsala university. (Marene Landström group)
Uppsala University. (Marene Landström group)
Vise andre og tillknytning
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Forskningsprogram
onkologi
Identifikatorer
URN: urn:nbn:se:umu:diva-87058OAI: oai:DiVA.org:umu-87058DiVA, id: diva2:705856
Tilgjengelig fra: 2014-03-18 Laget: 2014-03-18 Sist oppdatert: 2018-06-08bibliografisk kontrollert
Inngår i avhandling
1. TRAF6 stimulates TGFβ-induced oncogenic signal transduction in cancer cells
Åpne denne publikasjonen i ny fane eller vindu >>TRAF6 stimulates TGFβ-induced oncogenic signal transduction in cancer cells
2014 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Alternativ tittel[sv]
TRAF6 stimulerar TGFβ-inducerad onkogen signal transduction i cancerceller.
Abstract [en]

Prostate cancer is one of the leading causes of cancer-related deaths in men worldwide, with 10,000 new cases/year diagnosed in Sweden. In this context, there is an urgent need to identify new biomarkers to detect prostate cancer at an initial stage for earlier treatment intervention. Although how prostate cancer develops has not been fully established, the male sex hormone testosterone is a known prerequisite for prostate cancer development. High levels of transforming growth factor-β (TGFβ) are prognostically unfavorable in prostate cancer patients.

TGFβ is a multifunctional cytokine that regulates a broad range of cellular responses. TGFβ signals through either the canonical Smad or the non-Smad signaling cascade. Cancerous cells develop different strategies to evade defense mechanisms and metastasize to different parts of the body. This thesis unveils one such novel mechanism related to TGFβ signaling.

The first two articles provide evidence that TGFβ receptor type I (TβRI) is ubiquitinated by tumor necrosis factor receptor-associated factor 6 (TRAF6) and is cleaved at the ectodomain region by tumor necrosis factor alpha converting enzyme (TACE) in a protein kinase C zeta type-dependent manner. After TβRI is shed from the ectodomain, it undergoes a second cleavage by presenilin 1 (PS1), a γ-secretase catalytic subunit, which liberates the TβRI intracellular domain (TβRI-ICD) from the cell membrane. TRAF6 promotes TGFβ-dependent Lys63-linked polyubiquitination and recruitment of PS1 to the TβRI complex, and facilitates the cleavage of TβRI by PS1 to generate a TβRI-ICD. The TβRI-ICD then translocates to the nucleus, where it binds with the transcriptional co-activator p300 and regulates the transcription of pro-invasive target genes such as Snail1. Moreover, the nuclear translocated TβRI-ICD cooperates with the Notch intracellular domain (NICD), a core component in the Notch signaling pathway, to drive the expression of invasive genes. Interestingly, treatment with g-secretase inhibitors was able to inhibit cleavage of TβRI and inhibit the TGFβ-induced oncogenic pathway in an in vivo prostate cancer xenograft model.

In the third article, we identified that Lysine 178 is the acceptor lysine in TβRI that is ubiquitinated by TRAF6. The TβRI K178R mutant was neither ubiquitinated nor translocated to the nucleus, and prevented transcriptional regulation of invasive genes in a dominant negative manner.

In the fourth article, we show that TGFβ utilizes the E3-ligase TRAF6 and the p38 mitogen-activated protein kinase to phosphorylate c-Jun. In turn, the phosphorylated c-Jun activates p21 and Snail1 in a non-canonical Smad-independent pathway, and thereby promotes invasion in cancerous cells.

In summary, we elucidate a new mechanism of TGFβ-induced oncogenic signal transduction in cancer cells in which TRAF6 plays a fundamental role. This opens a new avenue in the field of TGFβ signaling.

sted, utgiver, år, opplag, sider
Umeå: Umeå University, 2014. s. 70
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1638
Emneord
c-Jun, invasion, non-Smad, Notch, NICD, oncogenesis, presenilin1, PKCζ, prostate cancer, p21, p38, p300, Snail1, TGFβ, TβRI, TACE, TRAF6, ubiquitination, TGFbeta signal transduction
HSV kategori
Forskningsprogram
patologi
Identifikatorer
urn:nbn:se:umu:diva-87017 (URN)978-91-7601-025-9 (ISBN)
Disputas
2014-04-11, Hörsal E 04, Unod R1, Norrlands universitetssjukhus, Umeå, 10:15 (engelsk)
Opponent
Veileder
Forskningsfinansiär
Swedish Cancer SocietySwedish Research Council
Tilgjengelig fra: 2014-03-19 Laget: 2014-03-18 Sist oppdatert: 2018-06-08bibliografisk kontrollert

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