Document Detail


Terminal differentiation and senescence in the human melanocyte: repression of tyrosine-phosphorylation of the extracellular signal-regulated kinase 2 selectively defines the two phenotypes.
MedLine Citation:
PMID:  8054689     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Melanocytes are pigmented cells distributed in humans in several organs like the epidermis, the leptomeninges, the eye, and the inner ear. Epidermal melanocytes, whether derived from adult or neonatal skin, proliferate well in a medium supplemented with phorbol esters and other mitogens before they undergo senescence. Potent cAMP inducers like cholera toxin are also growth promoters for neonatal melanocytes but only transient growth stimulators for cells derived from adults. We used this cellular system to delineate biochemical pathways involved in proliferation and in terminal differentiation. Here we show that after a period of 4-8 wk of sustained proliferation in the presence of cholera toxin, the adult melanocytes became round, flat, and enlarged. These changes were associated with terminal growth and preceded by a five- to sixfold increase in cAMP levels and an 8- to 10-fold increase in melanin content. The simultaneous addition of phorbol esters and cholera toxin did not prevent cells from reaching terminal differentiation. Identified targets for phorbol esters are protein kinase C (PKC) and the mitogen-activated kinases (MAPKs), also called extracellular signal-regulated kinases (ERKs). PKC was found to be similarly regulated in proliferating and in terminally differentiated melanocytes. Proliferating melanocytes in early or late passage showed identical activation of the kinase ERK2. This kinase was rapidly phosphorylated upon phorbol 12-myristate 13-acetate (PMA) addition and specifically accumulated in the nucleus of the cells, whereas in unstimulated cells it had a perinuclear distribution. In contrast, senescent and terminally differentiated cells were unable to phosphorylate tyrosine residues of the ERK2 gene product in spite of presenting normal amounts of ERK2 protein. In addition, ERK2 did not show the nuclear accumulation observed in proliferating melanocytes after PMA activation and remained localized in the perinuclear area. These results demonstrate that senescent and terminally differentiated melanocytes share a common block in a critical pathway thought to integrate multiple intracellular signals transmitted by various second messengers and specifically prevent the continuation of the signal transduction cascade initiated by PMA activation of PKC.
Authors:
E E Medrano; F Yang; R Boissy; J Farooqui; V Shah; K Matsumoto; J J Nordlund; H Y Park
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular biology of the cell     Volume:  5     ISSN:  1059-1524     ISO Abbreviation:  Mol. Biol. Cell     Publication Date:  1994 Apr 
Date Detail:
Created Date:  1994-09-14     Completed Date:  1994-09-14     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9201390     Medline TA:  Mol Biol Cell     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  497-509     Citation Subset:  IM    
Affiliation:
Department of Dermatology, University of Cincinnati College of Medicine, Ohio 45267.
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MeSH Terms
Descriptor/Qualifier:
Adult
Calcium-Calmodulin-Dependent Protein Kinases / analysis,  metabolism*
Cell Aging / physiology*
Cell Differentiation / physiology
Cell Nucleus / metabolism
Cells, Cultured
Cholera Toxin / pharmacology
Cyclic AMP / metabolism
Cytoplasm / metabolism
Enzyme Activation / drug effects
Humans
Infant, Newborn
Melanins / metabolism
Melanocytes / cytology*,  drug effects,  physiology*
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases*
Phosphorylation
Protein Kinase C / metabolism
Signal Transduction / physiology*
Tetradecanoylphorbol Acetate / pharmacology
Tyrosine / metabolism
Grant Support
ID/Acronym/Agency:
1K04 AGOO594-01/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Melanins; 16561-29-8/Tetradecanoylphorbol Acetate; 55520-40-6/Tyrosine; 60-92-4/Cyclic AMP; 9012-63-9/Cholera Toxin; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 2.7.11.24/Mitogen-Activated Protein Kinases
Comments/Corrections

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