Document Detail


Hematopoietic growth-factor signal transduction and regulation of gene expression.
MedLine Citation:
PMID:  2090258     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Hemopoietic cells have an absolute requirement for survival and proliferation for specific growth factors. The growth factors maintain the critical vitality of the cells by stimulating adenosine triphosphate (ATP) synthesis and hexose transport. Intracellular alkalinization also occurs rapidly through the stimulation of the Na+/H+ antiporter. These immediate metabolic events, not initiated by serum components, appear to be necessary for the integrity of cellular viability (Fig. 6). Interleukin-3 has been shown to induce the activation of PK-C through a mechanism(s) not requiring the hydrolysis of phosphoinositol 4,5 bisphosphate. A role for Ca2+ influx or intracellular release in the action of CSFs or interleukins has not been shown. Although downregulation of cAMP has been reported in response to IL-2, the signal transduction process of CSFs and IL-2 appears not to be mediated by upregulation of cyclic nucleotide metabolism or "classical" phospholipid degradative pathways. Protein phosphorylation is clearly modulated by the hemopoietic cytokines, yet only the CSF-1 receptor has any known intrinsic kinase activity. Instead, the IL-3, GM-CSF receptors, and perhaps G-CSF appear to be coupling to kinases of both tyrosine and serine specificities. This may be a direct allosteric interaction with membrane-associated kinases or transduced through an intermediate protein such as those using GTP. Such is the case for many hormone receptors that couple to amplifying "second messenger" enzyme systems (i.e., adenylate cyclase, phospholipase C) or members of the insulin growth factor family that couple to tyrosine kinases in proximity to the receptors (IGF-II). One of the kinase systems that IL-2, IL-3, and other CSFs stimulate appears to have some characteristics similar to PK-C. Direct activators of PK-C stimulate some similar serine-threonine phosphorylation and perhaps even tyrosine phosphorylation. The hemopoietic growth factors, however, stimulate tyrosine phosphorylation of some proteins that are not phosphorylated in response to PK-C activators, suggesting that these kinase systems are independently regulated. Although phorbol esters stimulate many of the same metabolic activities (ATP synthesis in myeloid and lymphoid cell lines), growth-factor abrogation is clearly associated with the action of tyrosine kinase oncogenes or the nuclear oncogene effectors such as v-myc. It is likely, therefore, that tyrosine kinases are playing a critical role in the control of proliferation although the dominant amount of cellular protein phosphorylations are on serine. Both classes of kinases are apparently required for growth-factor action. All the hemopoietic growth factors examined thus far stimulate the steady-state accumulation of the nuclear protooncogenes.(ABSTRACT TRUNCATED AT 400 WORDS)
Authors:
W L Farrar; A T Brini; A Harel-Bellan; M Korner; D K Ferris
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.; Review    
Journal Detail:
Title:  Immunology series     Volume:  49     ISSN:  0092-6019     ISO Abbreviation:  Immunol. Ser.     Publication Date:  1990  
Date Detail:
Created Date:  1991-06-04     Completed Date:  1991-06-04     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0404721     Medline TA:  Immunol Ser     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  379-410     Citation Subset:  IM    
Affiliation:
National Cancer Institute-Frederick Cancer Research Facility, Maryland.
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MeSH Terms
Descriptor/Qualifier:
Animals
Gene Expression Regulation
Hematopoietic Cell Growth Factors / genetics,  physiology*
Humans
Phosphorylation
Proteins / metabolism
Receptors, Colony-Stimulating Factor / physiology
Signal Transduction
Grant Support
ID/Acronym/Agency:
N01-CO-74102/CO/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Hematopoietic Cell Growth Factors; 0/Proteins; 0/Receptors, Colony-Stimulating Factor

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