New and unexpected: forkhead meets ARF.
Recent genetic studies demonstrate that mice deficient in the forkhead box m1b (Foxm1b) transcription factor are highly resistant to developing hepatocellular carcinoma, which is among the most lethal cancers worldwide. In addition, the Foxm1b transcription factor was identified as a novel inhibitory target of the p19ARF tumor suppressor during early stages of liver tumorigenesis, but p19ARF expression is extinguished in hepatic tumors that develop at later stages. Structure-function studies demonstrate that amino acids 26-46 of the p19ARF protein are sufficient to bind Foxm1b and reduce Foxm1b transcriptional activity by targeting it to the nucleolus. A peptide containing amino acids 24-46 of p19ARF, which was modified to enhance cellular uptake, is an effective inhibitor of Foxm1b transcriptional activity and prevents Foxm1b stimulation of anchorage-independent growth of cells on soft agar. Thus, the p19ARF peptide is an effective inhibitor of Foxm1b and represents a potential therapy for hepatocellular carcinoma.
Costa
Robert H
RH
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60607, USA. robcosta@uic.edu
Kalinichenko
Vladimir V
VV
Major
Michael L
ML
Raychaudhuri
Pradip
P
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
C493961:Cdkn1b protein, mouse; C417743:Cdkn2a protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D048031:JNK Mitogen-Activated Protein Kinases