TMEM33: a new stress-inducible endoplasmic reticulum transmembrane protein and modulator of the unfolded protein response signaling

Autor: Rong Hu, Isamu Sakabe, Robert Clarke, Lu Jin, Usha Kasid
Rok vydání: 2015
Předmět:
X-Box Binding Protein 1
Cancer Research
TMEM33
Eukaryotic Initiation Factor-2
Gene Expression
eIF-2 Kinase
0302 clinical medicine
Preclinical Study
Breast cancer
0303 health sciences
Endoplasmic Reticulum Stress
Transmembrane protein
3. Good health
Transport protein
Cell biology
DNA-Binding Proteins
Protein Transport
Oncology
030220 oncology & carcinogenesis
Female
Signal transduction
Endoplasmic reticulum stress and unfolded protein response
Signal Transduction
Caspase-7
PERK
endocrine system
XBP1
Recombinant Fusion Proteins
Molecular Sequence Data
Breast Neoplasms
Regulatory Factor X Transcription Factors
Biology
Protein Serine-Threonine Kinases
03 medical and health sciences
Cell Line
Tumor
Endoribonucleases
Autophagy
Animals
Humans
Amino Acid Sequence
030304 developmental biology
Base Sequence
Endoplasmic reticulum
Membrane Proteins
IRE1α
Molecular biology
Activating Transcription Factor 4
Unfolded protein response
Unfolded Protein Response
Transcription Factors
Zdroj: Breast Cancer Research and Treatment
ISSN: 1573-7217
Popis: Endoplasmic reticulum (ER) stress leads to activation of the unfolded protein response (UPR) signaling cascade and induction of an apoptotic cell death, autophagy, oncogenesis, metastasis, and/or resistance to cancer therapies. Mechanisms underlying regulation of ER transmembrane proteins PERK, IRE1α, and ATF6α/β, and how the balance of these activities determines outcome of the activated UPR, remain largely unclear. Here, we report a novel molecule transmembrane protein 33 (TMEM33) and its actions in UPR signaling. Immunoblotting and northern blot hybridization assays were used to determine the effects of ER stress on TMEM33 expression levels in various cell lines. Transient transfections, immunofluorescence, subcellular fractionation, immunoprecipitation, and immunoblotting were used to study the subcellular localization of TMEM33, the binding partners of TMEM33, and the expression of downstream effectors of PERK and IRE1α. Our data demonstrate that TMEM33 is a unique ER stress-inducible and ER transmembrane molecule, and a new binding partner of PERK. Exogenous expression of TMEM33 led to increased expression of p-eIF2α and p-IRE1α and their known downstream effectors, ATF4-CHOP and XBP1-S, respectively, in breast cancer cells. TMEM33 overexpression also correlated with increased expression of apoptotic signals including cleaved caspase-7 and cleaved PARP, and an autophagosome protein LC3II, and reduced expression of the autophagy marker p62. TMEM33 is a novel regulator of the PERK-eIE2α-ATF4 and IRE1-XBP1 axes of the UPR signaling. Therefore, TMEM33 may function as a determinant of the ER stress-responsive events in cancer cells. Electronic supplementary material The online version of this article (doi:10.1007/s10549-015-3536-7) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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