Abstract
Blocked differentiation is a hallmark of cancer cells and the restoration of differentiation programs in vivo is an actively pursued clinical aim. Understanding the key regulators of cyto-differentiation may focus therapies on molecules that reactivate this process. c-myb expression declines rapidly when human colon cancer epithelial cells are induced to differentiate with the physiologically relevant short-chain fatty acid, sodium butyrate. These cells show increased expression of alkaline phosphatase and cytokeratin 8. Similarly, murine Immorto-epithelial cells derived from wild-type colon cells also show c-myb mRNA declines when induced to differentiate with sodium butyrate. Immorto-cells harboring a single APC mutation are indistinguishable from wild-type cells with regard to differentiation, while addition of activated RAS alone markedly enhances differentiation. In marked contrast, complete differentiation arrest occurs when both APC and RAS are mutated. Expression of MybER, a 4-hydroxytamoxifen-activatable form of c-Myb, blocks differentiation in wildtype and APC mutant Immorto-cell lines as well as LIM1215 human colon carcinoma cells. These data identify two pathways of oncogenic change that lead to retarded epithelial cell differentiation, one involving the presence of a single APC mutation in conjunction with activated RAS or alternatively constitutive c-myb expression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenomatous Polyposis Coli Protein / genetics*
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Adenomatous Polyposis Coli Protein / metabolism
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Alkaline Phosphatase / analysis
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Alkaline Phosphatase / metabolism
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Animals
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Butyrates / pharmacology
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Cell Differentiation
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Cell Nucleus / chemistry
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Colon / cytology*
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Colonic Neoplasms / genetics*
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Colonic Neoplasms / metabolism
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Cytoskeletal Proteins / analysis
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Cytoskeletal Proteins / metabolism
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Cytosol / chemistry
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Down-Regulation / genetics
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Epithelial Cells / cytology
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Gene Expression / genetics
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Genes, ras / genetics*
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Humans
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Intercellular Signaling Peptides and Proteins / analysis
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Intercellular Signaling Peptides and Proteins / metabolism
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Intestinal Mucosa / cytology*
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / metabolism
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Mice
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Mutation / genetics
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Proto-Oncogene Proteins c-myb / genetics*
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Proto-Oncogene Proteins c-myb / metabolism
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RNA, Messenger / analysis
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RNA, Messenger / metabolism
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Trans-Activators / analysis
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Trans-Activators / metabolism
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / analysis
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Tumor Suppressor Protein p53 / metabolism
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Wnt Proteins
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beta Catenin
Substances
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Adenomatous Polyposis Coli Protein
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Butyrates
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Cytoskeletal Proteins
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Intercellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins c-myb
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RNA, Messenger
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Trans-Activators
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Tumor Suppressor Protein p53
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Wnt Proteins
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beta Catenin
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Alkaline Phosphatase