Tylophorine Analog DCB-3503 Inhibited Cyclin D1 Translation through Allosteric Regulation of Heat Shock Cognate Protein 70.
Tylophorine analog DCB-3503 is a potential anticancer and immunosuppressive agent that suppresses the translation of cellular regulatory proteins, including cyclin D1, at the elongation step. However, the molecular mechanism underlying this phenomenon remains unknown. This study demonstrates that DCB-3503 preferentially binds to heat shock cognate protein 70 (HSC70), which is a determinant for cyclin D1 translation by binding to the 3'-untranslated region (3' UTR) of its mRNA. DCB-3503 allosterically regulates the ATPase and chaperone activities of HSC70 by promoting ATP hydrolysis in the presence of specific RNA binding motifs (AUUUA) of cyclin D1 mRNA. The suppression of cyclin D1 translation by DCB-3503 is not solely caused by perturbation of the homeostasis of microRNAs, although the microRNA processing complex is dissociated with DCB-3503 treatment. This study highlights a novel regulatory mechanism of protein translation with AUUUA motifs in the 3' UTR of mRNA by HSC70, and its activity can be allosterically modulated by DCB-3503. DCB-3503 may be used to treat malignancies, such as hepatocellular carcinoma or breast cancer with elevated expression of cyclin D1.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.|State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao SAR, China.
Ying
Y
Wang
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Wing
W
Lam
State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao SAR, China.
Shao-Ru
SR
Chen
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Fu-Lan
FL
Guan
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Ginger E
GE
Dutchman
Department of Chemistry, The University of Tennessee, Knoxville, TN 37996, USA.
Samson
S
Francis
Department of Chemistry, The University of Tennessee, Knoxville, TN 37996, USA.
David C
DC
Baker
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Yung-Chi
YC
Cheng
D020413:3' Untranslated Regions / Q000235:genetics; D000494:Allosteric Regulation; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007212:Indolizines / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D020413:3' Untranslated Regions; C530104:CCND1 protein, human; C509364:DCB 3503; D050883:HSC70 Heat-Shock Proteins; D007212:Indolizines; D010616:Phenanthrenes; D019938:Cyclin D1