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Scaffold protein FHL2 facilitates MDM2-mediated degradation of IER3 to regulate proliferation of cervical cancer cells
- Source :
- Oncogene
- Publication Year :
- 2016
- Publisher :
- Springer Science and Business Media LLC, 2016.
-
Abstract
- The expression of immediate early response 3 (IER3), a protein with a short half-life, is rapidly induced by various cellular stimuli. We recently reported that IER3 induces the apoptosis of cervical cancer cells and that its expression is downregulated in patients with cervical cancer. However, the molecular mechanism involved in the rapid degradation of IER3 remains unknown. Here, we demonstrate that MDM2 is an E3 ligase that interacts with IER3 and promotes its ubiquitination, followed by proteasomal degradation. Polyubiquitination of the conserved lysine 60 of IER3 is essential for its degradation. In addition, four and a half LIM domains protein 2 (FHL2) binds to both IER3 and MDM2, allowing for efficient MDM2-mediated IER3 degradation by facilitating an association between MDM2 and IER3. Moreover, IER3 induces cell cycle arrest in cervical cancer cells and its activity is further enhanced in cells in which FHL2 or MDM2 was silenced, thereby preventing IER3 degradation. The E6 and E7 oncoproteins of human papilloma virus 18 regulated IER3 expression. FHL2 expression was significantly higher in the squamous epithelium of cervical carcinoma tissues than in non-cancerous cervical tissues, whereas cervical carcinoma expression of IER3 was downregulated in this region. Thus, we determined the molecular mechanism responsible for IER3 degradation, involving a ternary complex of IER3, MDM2 and FHL2, which may contribute to cervical tumor growth. Furthermore, we demonstrated that FHL2 serves as a scaffold for E3 ligase and its substrate during the ubiquitination reaction, a function that has not been previously reported for this protein.
- Subjects :
- 0301 basic medicine
Scaffold protein
Proteasome Endopeptidase Complex
Cancer Research
IER3
LIM-Homeodomain Proteins
Muscle Proteins
Uterine Cervical Neoplasms
03 medical and health sciences
Ubiquitin
Proto-Oncogene Proteins c-mdm2
Genetics
Humans
Molecular Biology
Cell Proliferation
Human papillomavirus 18
biology
Ubiquitination
Membrane Proteins
Oncogene Proteins, Viral
Cell cycle
Ubiquitin ligase
FHL2
DNA-Binding Proteins
Gene Expression Regulation, Neoplastic
030104 developmental biology
Proteolysis
biology.protein
Cancer research
Mdm2
Female
Original Article
Apoptosis Regulatory Proteins
HeLa Cells
Transcription Factors
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 35
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....55726d67c5eb2e2a9c4cbde152a5f9aa