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IER3 is a crucial mediator of TAp73β-induced apoptosis in cervical cancer and confers etoposide sensitivity.
- Source :
-
Scientific reports [Sci Rep] 2015 Feb 10; Vol. 5, pp. 8367. Date of Electronic Publication: 2015 Feb 10. - Publication Year :
- 2015
-
Abstract
- Infection with high-risk human papillomaviruses (HPVs) causes cervical cancer. E6 oncoprotein, an HPV gene product, inactivates the major gatekeeper p53. In contrast, its isoform, TAp73β, has become increasingly important, as it is resistant to E6. However, the intracellular signaling mechanisms that account for TAp73β tumor suppressor activity in cervix are poorly understood. Here, we identified that IER3 is a novel target gene of TAp73β. In particular, TAp73β exclusively transactivated IER3 in cervical cancer cells, whereas p53 and TAp63 failed to do. IER3 efficiently induced apoptosis, and its knockdown promoted survival of HeLa cells. In addition, TAp73β-induced cell death, but not p53-induced cell death, was inhibited upon IER3 silencing. Moreover, etoposide, a DNA-damaging chemotherapeutics, upregulated TAp73β and IER3 in a c-Abl tyrosine kinase-dependent manner, and the etoposide chemosensitivity of HeLa cells was largely determined by TAp73β-induced IER3. Of interest, cervical carcinomas from patients express no observable levels of two proteins. Thus, our findings suggest that IER3 is a putative tumor suppressor in the cervix, and the c-Ab1/p73β/IER3 axis is a novel and crucial signaling pathway that confers etoposide chemosensitivity. Therefore, TAp73β and IER3 induction would be a valuable checkpoint for successful therapeutic intervention of cervical carcinoma patients.
- Subjects :
- Apoptosis Regulatory Proteins genetics
DNA-Binding Proteins genetics
Drug Resistance, Neoplasm genetics
Female
HeLa Cells
Humans
Membrane Proteins genetics
Nuclear Proteins genetics
Tumor Protein p73
Tumor Suppressor Proteins genetics
Uterine Cervical Neoplasms genetics
Uterine Cervical Neoplasms metabolism
Uterine Cervical Neoplasms pathology
Antineoplastic Agents, Phytogenic pharmacology
Apoptosis drug effects
Apoptosis Regulatory Proteins metabolism
DNA-Binding Proteins metabolism
Drug Resistance, Neoplasm drug effects
Etoposide pharmacology
Membrane Proteins metabolism
Nuclear Proteins metabolism
Tumor Suppressor Proteins metabolism
Uterine Cervical Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 5
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 25666857
- Full Text :
- https://doi.org/10.1038/srep08367