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Tid1-L inhibits EGFR signaling in lung adenocarcinoma by enhancing EGFR Ubiquitinylation and degradation.
- Source :
-
Cancer research [Cancer Res] 2013 Jul 01; Vol. 73 (13), pp. 4009-19. Date of Electronic Publication: 2013 May 22. - Publication Year :
- 2013
-
Abstract
- Tid1 (DNAJA3), a DnaJ cochaperone, may promote degradation of oncogenic kinases. Tid1 has 2 isoforms, Tid1-L and Tid1-S, that may function differently. In this study, we investigated the role of the Tid1 isoforms in regulating EGF receptor (EGFR) signaling and lung cancer progression. We found that both Tid1-L and Tid1-S expressions were reduced in patients with non-small cell lung cancer compared with normal counterparts. Tid1-L expression correlated inversely with EGFR expression. Low Tid1-L/high EGFR expression predicted poor overall survival in patients with lung adenocarcinoma. Tid1-L overexpression in lung cancer cells attenuated EGFR signaling and inhibited cell proliferation, colony formation, and tumor growth in subcutaneous and orthotropic xenograft models. Conversely, depletion of Tid1 restored EGFR signaling and increased cell proliferation and colony formation. Tid1-L, but not Tid1-S, interacted with EGFR/HSP70/HSP90 through the DnaJ domain, counteracting the EGFR regulatory function of HSP90 by causing EGFR ubiquitinylation and proteasomal degradation. Tid1-L inhibited EGFR signaling even more than the HSP90 inhibitor 17-allylamino-demethoxy geldanamycin. We concluded that Tid1-L acted as a tumor suppressor by inhibiting EGFR signaling through interaction with EGFR/HSP70/HSP90 and enhancing EGFR ubiquitinylation and degradation.<br /> (©2013 AACR.)
- Subjects :
- Adenocarcinoma mortality
Adenocarcinoma of Lung
Animals
Apoptosis
Cell Line, Tumor
Cell Proliferation
Epidermal Growth Factor physiology
Female
Gene Expression
HSP40 Heat-Shock Proteins chemistry
HSP70 Heat-Shock Proteins metabolism
HSP90 Heat-Shock Proteins metabolism
Humans
Kaplan-Meier Estimate
Lung Neoplasms mortality
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Multivariate Analysis
Neoplasm Transplantation
Polyubiquitin metabolism
Protein Isoforms chemistry
Protein Isoforms physiology
Protein Structure, Tertiary
Signal Transduction
Adenocarcinoma metabolism
ErbB Receptors metabolism
HSP40 Heat-Shock Proteins physiology
Lung Neoplasms metabolism
Proteolysis
Ubiquitination
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 73
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 23698466
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-12-4066