期刊
BIOMOLECULES
卷 11, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/biom11060860
关键词
human medullary thyroid carcinoma; CDK5/p35; RET; STAT3; ERK1/2; EGR1
资金
- Tung's Taichung Metro Harbor Hospital, Taiwan [TTMHH-NCHULS108004]
- Ministry of Science and Technology, Taiwan [MOST-109-2320-B-005-004-MY3, MOST-109-2911-I-005-503]
- Taichung Veterans General Hospital/NCHU Joint Research Program [TCVGH-NCHU1097610]
In our study, we investigated the RET activation and its biochemical interaction with CDK5 in GDNF-induced medullary thyroid cancer proliferation. Additionally, we identified the physical interaction between CDK5 and RET protein in MTC for the first time.Overall, our results suggest that targeting CDK5 may be a promising therapeutic candidate for human medullary thyroid cancer in the near future.
Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the parafollicular C-cells, which produces the hormone calcitonin. RET is a transmembrane receptor protein-tyrosine kinase, which is highly expressed in MTC. Our previous studies reported that cyclin-dependent kinase 5 (CDK5) plays a crucial role in cancer progression, including MTC. However, the role of CDK5 in GDNF-induced RET signaling in medullary thyroid cancer proliferation remains unknown. Here, we investigated RET activation and its biochemically interaction with CDK5 in GDNF-induced medullary thyroid cancer proliferation. Our results demonstrated that GDNF stimulated RET phosphorylation and thus subsequently resulted in CDK5 activation by its phosphorylation. Activated CDK5 further caused STAT3 activation by its specific phosphorylation at Ser727. Moreover, we also found that GDNF treatment enhanced ERK1/2 and EGR1 activity, which is involved in p35 activation. Interestingly, we identified for the first time that CDK5 physically interacted with RET protein in MTC. Overall, our results provide a new mechanism for medullary thyroid cancer cell proliferation, suggesting that targeting CDK5 may be a promising therapeutic candidate for human medullary thyroid cancer in the near future.
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