Epidermal growth factor promotes cyclin G2 degradation via calpain-mediated proteolysis in gynaecological cancer cells

Cyclin G2 (CCNG2) is an atypical cyclin that functions to inhibit cell cycle progression and is often dysregulated in human cancers. We have previously shown that cyclin G2 is highly unstable and can be degraded through the ubiquitin/proteasome pathway. Furthermore, cyclin G2 contains a PEST domain,...

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Published in:	PloS one Vol. 12; no. 6; p. e0179906
Main Authors:	Bernaudo, Stefanie, Khazai, Shahin, Honarparvar, Eilyad, Kopteva, Alina, Peng, Chun
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 22-06-2017 Public Library of Science (PLoS)
Subjects:	Amino Acid Sequence Animals Biology Biology and Life Sciences Calcium Calcium (intracellular) Calcium content Calpain Calpain - metabolism Cancer Cell cycle Cell division Cell Line, Tumor Cervical cancer Cyclin G2 - chemistry Cyclin G2 - metabolism Degradation Destruction Drug Screening Assays, Antitumor Enzyme inhibitors Epidermal growth factor Epidermal Growth Factor - pharmacology Epidermal growth factors Female Gynecological cancer Humans Kinases Libraries Lysates Medical screening Ovarian cancer Pests Phosphorylation Phosphorylation - drug effects Plasmids Proteasomes Protein Domains Proteins Proteolysis Proteolysis - drug effects Receptor, Epidermal Growth Factor - metabolism Research and Analysis Methods siRNA Ubiquitin Uterine Cervical Neoplasms - pathology
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Summary:	Cyclin G2 (CCNG2) is an atypical cyclin that functions to inhibit cell cycle progression and is often dysregulated in human cancers. We have previously shown that cyclin G2 is highly unstable and can be degraded through the ubiquitin/proteasome pathway. Furthermore, cyclin G2 contains a PEST domain, which has been suggested to act as a signal for degradation by multiple proteases. In this study, we determined if calpains, a family of calcium-dependent proteases, are also involved in cyclin G2 degradation. The addition of calpain inhibitors or silencing of calpain expression by siRNAs strongly enhanced cyclin G2 levels. On the other hand, incubation of cell lysates with purified calpains or increasing the intracellular calcium concentration resulted in a decrease in cyclin G2 levels. Interestingly, the effect of calpain was found to be dependent on the phosphorylation of cyclin G2. Using a kinase inhibitor library, we found that Epidermal Growth Factor (EGF) Receptor is involved in cyclin G2 degradation and treatment with its ligand, EGF, induced cyclin G2 degradation. In addition, the presence of the PEST domain is necessary for calpain and EGF action. When the PEST domain was completely removed, calpain or EGF treatment failed to trigger degradation of cyclin G2. Taken together, these novel findings demonstrate that EGF-induced, calpain-mediated proteolysis contributes to the rapid destruction of cyclin G2 and that the PEST domain is critical for EGF/calpain actions.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceptualization: CP SB.Formal analysis: SB SK.Funding acquisition: CP.Investigation: SB SK EH AK.Methodology: SB CP.Project administration: CP.Resources: CP.Supervision: CP.Validation: SB SK EH AK.Visualization: SB SK CP.Writing – original draft: SB CP.Writing – review & editing: SB SK EH AK CP. Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0179906