Expression and characterization of Syrian golden hamster p16, a homologue of human tumor suppressor p16 INK4A.
The p16(INK4A)/CDKN2A tumor suppressor gene is known to be inactivated in up to 98% of human pancreatic cancer specimens and represents a potential target for novel therapeutic intervention. Chemically induced pancreatic tumors in Syrian golden hamsters have been demonstrated to share many morphologic and biological similarities with human pancreatic tumors and this model may be appropriate for studying therapies targeting p16(INK4A)/CDKN2A. The purpose of this study was to investigate the fundamental biochemistry of hamster P16 protein. Using both in vivo and in vitro approaches, the CDK4 binding affinity, kinase inhibitory activity, and thermodynamic stability of hamster and human P16 proteins were evaluated. Furthermore, a structural model of hamster P16 protein was generated. These studies demonstrate that hamster P16 protein is biochemically indistinguishable from human P16 protein. From a biochemical perspective, these data strongly support the study of p16-related pancreatic oncogenesis and cancer therapies in the hamster model.
Li
Junan
J
Department of Surgery, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210, USA. muscarella-l@medctr.osu.edu
Qin
Dongyan
D
Knobloch
Thomas J
TJ
Tsai
Ming-Daw
MD
Weghorst
Christopher M
CM
Melvin
W Scott
WS
Muscarella
Peter
P
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D006224:Cricetinae; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008647:Mesocricetus; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins; D017386:Sequence Homology, Amino Acid; D020798:Two-Hybrid System Techniques
D019941:Cyclin-Dependent Kinase Inhibitor p16; D011518:Proto-Oncogene Proteins; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases