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PMID: 15082532 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor.

Genes & development ·Vol. 18 ·No. 7 ·2004-04-01 ·Pages 830-50

Kalinichenko VV, Major ML, Wang X, Petrovic V, Kuechle J, Yoder HM, Dennewitz MB, Shin B, Datta A, Raychaudhuri P, Costa RH

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Here, we provide evidence that the Forkhead Box (Fox) m1b (Foxm1b or Foxm1) transcription factor is essential for the development of HCC. Conditionally deleted Foxm1b mouse hepatocytes fail to proliferate and are highly resistant to developing HCC in response to a Diethylnitrosamine (DEN)/Phenobarbital (PB) liver tumor-induction protocol. The mechanism of resistance to HCC development is associated with nuclear accumulation of the cell cycle inhibitor p27(Kip1) protein and reduced expression of the Cdk1-activator Cdc25B phosphatase. We showed that the Foxm1b transcription factor is a novel inhibitory target of the p19(ARF) tumor suppressor. Furthermore, we demonstrated that conditional overexpression of Foxm1b protein in osteosarcoma U2OS cells greatly enhances anchorage-independent growth of cell colonies on soft agar. A p19(ARF) 26-44 peptide containing nine D-Arg to enhance cellular uptake of the peptide was sufficient to significantly reduce both Foxm1b transcriptional activity and Foxm1b-induced growth of U2OS cell colonies on soft agar. These results suggest that this (D-Arg)(9)-p19(ARF) 26-44 peptide is a potential therapeutic inhibitor of Foxm1b function during cellular transformation. Our studies demonstrate that the Foxm1b transcription factor is required for proliferative expansion during tumor progression and constitutes a potential new target for therapy of human HCC tumors.

MeSH Terms
Adenoma/genetics,pathology Alkylating Agents/toxicity Animals Apoptosis Calcium-Binding Proteins/metabolism Carcinoma, Hepatocellular/genetics,pathology Cell Cycle Proteins/metabolism Cell Nucleus/metabolism Colony-Forming Units Assay Cyclin-Dependent Kinase Inhibitor p16 Cyclin-Dependent Kinase Inhibitor p27 DNA-Binding Proteins/physiology Disease Progression Excitatory Amino Acid Antagonists/toxicity Eye Proteins Female Forkhead Box Protein M1 Forkhead Transcription Factors Genes, p16 Glutathione S-Transferase pi Glutathione Transferase/metabolism Hepatocytes/metabolism Hippocalcin Humans Isoenzymes/metabolism Lipoproteins Liver Neoplasms, Experimental/genetics,pathology Male Mice Mice, Inbred C57BL Mice, Transgenic Nerve Tissue Proteins Osteosarcoma/metabolism,pathology Peptide Fragments/pharmacology Recoverin Transcription Factors/antagonists & inhibitors,genetics,physiology Tumor Suppressor Protein p14ARF/pharmacology Tumor Suppressor Proteins/metabolism cdc25 Phosphatases/metabolism
Chemicals
Alkylating Agents Calcium-Binding Proteins Cdkn1b protein, mouse Cdkn2a protein, mouse Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p16 DNA-Binding Proteins Excitatory Amino Acid Antagonists Eye Proteins FOXM1 protein, human Forkhead Box Protein M1 Forkhead Transcription Factors Foxm1 protein, mouse Isoenzymes Lipoproteins Nerve Tissue Proteins Peptide Fragments RCVRN protein, human Rcvrn protein, mouse Transcription Factors Tumor Suppressor Protein p14ARF Tumor Suppressor Proteins Recoverin Cyclin-Dependent Kinase Inhibitor p27 Hippocalcin GSTP1 protein, human Glutathione S-Transferase pi Glutathione Transferase Gstp1 protein, mouse CDC25B protein, human cdc25 Phosphatases
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Kalinichenko Vladimir V
University of Illinois at Chicago, College of Medicine, Department of Biochemistry and Molecular Genetics, Chicago, Illinois 60607, USA.
Major Michael L
Wang Xinhe
Petrovic Vladimir
Kuechle Joseph
Yoder Helena M
Dennewitz Margaret B
Shin Brian
Datta Abhishek
Raychaudhuri Pradip
Costa Robert H
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1200704
Published
2004-04-01
Pages
830-50
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC387422
Subset
IM
Grants
NIA NIH HHS · R01 AG021842 · United States
NIDDK NIH HHS · R01 DK054687 · United States
NIDDK NIH HHS · DK 54687-06 · United States
NIA NIH HHS · R01 AG 21842-02 · United States
External Links
PubMed source DOI: 10.1101/gad.1200704 PMC Full Text View journal details
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