Document Detail


Retrodifferentiation--an alternative biological pathway in human leukemia cells.
MedLine Citation:
PMID:  1644056     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Human myeloid leukemia cells (i.e., HL-60, U937, THP-1) which are induced to differentiate along the monocytic pathway by 12-O-tetradecanoylphorbol-13-acetate (TPA), revert back to the undifferentiated phenotype after 3 to 4 weeks. During this differentiation and retrodifferentiation process the cells obviously establish a distinct sequence of biological processes which is integrally regulated to simultaneously control differentiation and cell growth. Thus, induction of monocytic markers by TPA is associated with a down-regulation of cell cycle genes and cessation of proliferation. In particular, crosstalk between the TPA-induced translocation of protein kinase C (PKC) and the activation of transcription factors, especially AP-1, enhances the expression of genes associated with the monocytic phenotype. This is accompanied by induction of intermediate filament proteins, surface glycoproteins, changes in membrane properties and intracellular metabolism. In parallel, the cells cease to divide, and genes associated with cell cycle progression including cdc2, cyclins, cdc25, and histones are down-regulated. Although signals responsible for arrested cell growth remain unclear, there are several control mechanisms regarding cell cycle genes and differentiation parameters (for a review, see Nigg, E. A., Seminars in Cell Biol., 2, 262-270, 1991). For example, activated p34cdc2 kinase is involved in lamina disassembly by direct phosphorylation of lamin proteins which may contribute to nuclear envelope breakdown during mitosis (Enoch, T., M. Peter, P. Nurse, J. Cell Biol. 112, 797-807 (1991)). Moreover, endomembrane traffic is arrested by a cdc2-like kinase probably via phosphorylation of members of the rab protein family which contributes to vesiculation and membrane transport by hydrolyzing GTP (Tuomikoski, T., et al., Nature 342, 942-945 (1989)). Although there are several reports on a possible feedback control between differentiation and cell cycle, including phosphorylation of cyclins and activation of a ubiquitin-dependent proteolytic degradation, signaling pathways and possible mechanisms for retrodifferentiation and reentry into the cell cycle remain unclear. While some terminally differentiated cells are committed to die, the major part of the differentiated monocytic population undergoes retrodifferentiation. All cellular signals characterized so far are reverted during retrodifferentiation: Redistribution of PKC and down-regulation of c-fos and c-jun contribute to an interruption of the differentiation-associated transsignaling cascade. Thus, down-regulation of markers associated with monocytic differentiation in combination with metabolic changes restore the original cell phenotype. At the same time cell cycle genes are up-regulated, and the cells regain proliferative capacity. Finally, retrodifferentiated and untreated control cells demonstrate indistinguishable properties.
Authors:
R Hass
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  European journal of cell biology     Volume:  58     ISSN:  0171-9335     ISO Abbreviation:  Eur. J. Cell Biol.     Publication Date:  1992 Jun 
Date Detail:
Created Date:  1992-09-10     Completed Date:  1992-09-10     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7906240     Medline TA:  Eur J Cell Biol     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  1-11     Citation Subset:  IM    
Affiliation:
Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
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MeSH Terms
Descriptor/Qualifier:
Cell Cycle / physiology
Cell Death / physiology
Cell Differentiation / physiology*
Gene Expression Regulation, Neoplastic / physiology
Glycoproteins / physiology
Humans
Leukemia, Myeloid / pathology*
Protein Kinase C / physiology
Signal Transduction
Transcription Factors / physiology
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Glycoproteins; 0/Transcription Factors; EC 2.7.11.13/Protein Kinase C

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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