UMEÅ UNIVERSITY MEDICAL DISSERTATIONS
New Series No. 1638 ISSN 0346-6612 ISBN 978-91-7601-025-9
TRAF6 stimulates TGFβ-induced oncogenic signal transduction in cancer cells
Shyam Kumar Gudey
Akademisk avhandling
Som med vedebörlight tillstånd av Rektor vid Umea Universitet för avläggande av medicine doktorexamen framläggs till offentligt försvar i hörsal E 04 Unod R1, Norrlands
universitetssjukhus, fredagen den 11 april 2014, kl. 10:15 Avhandlingen kommer att försvaras på engelska
Fakultetsopponent: Professor Urban Lendahl, Department of Cell and Molecular Biology (CMB), Karolinska Institute, Stockholm, Sweden
Department of Medical Biosciences, Pathology Umeå University, Umeå 2014
Organization Document Type Date of publication Umeå University Doctoral thesis 19 March, 2014 Author
Shyam Kumar Gudey Title
TRAF6 stimulates TGFβ-induced oncogenic signal transduction in cancer cells Abstract
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.
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.
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 ζ 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. 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 γ-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 as 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 the transcription factor 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.
Keywords: c-Jun, invasion, non-Smad, Notch, NICD, oncogenesis, presenilin1, PKCζ, prostate cancer, p21, p38, p300, Snail1,TGFβ, TβRI, TACE, TRAF6, ubiquitination.
Language ISBN ISSN Number of pages English 978-91-7601-025-9 0346-6612 70 + 4 papers
