Document Detail


Dual role of hematopoietic progenitor kinase 1 (HPK1) as a positive regulator of 1α,25-dihydroxyvitamin D-induced differentiation and cell cycle arrest of AML cells and as a mediator of vitamin D resistance.
MedLine Citation:
PMID:  22421156     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Recent clinical trials aimed at improved treatment of AML by administration of vitamin D derivatives showed unremarkable results, suggesting development of vitamin D resistance in patients' AML blasts. Since mechanisms of vitamin D resistance are not clear, we studied 40AF cells, a subline of HL60 cells that can proliferate in the presence of 1α,25-dihydroxyvitamin D₃ (1,25D). We found that mRNA and protein levels of HPK1, an upstream MAP4 kinase, are dramatically increased in 40AF cells, and HPK1 protein is further increased when the 1,25D resistance of 40AF cells is partially reversed by the addition of carnosic acid and p38MAPK inhibitor SB202190 (DCS cocktail). Knockdown of HPK1 reduces 1,25D/DCS-induced differentiation of both 1,25D-sensitive HL60 and U937 cells and 1,25D-resistant 40AF cells, but the effect of HPK1 knockdown on differentiation-associated G 1 arrest is more apparent in the resistant than the sensitive cells. To explain why 40AF and the intrinsically vitamin D-resistant KG-1a cells can proliferate in the presence of vitamin D, we found that the cleaved HPK1 fragment (HPK1-C) level is high in 40AF and KG-1a cells, but when differentiation is induced by DCS, HPK1-C decreases while full-length (FL)-HPK1 increases. Accordingly, inhibition of proteolysis with the pan-caspase inhibitor Q-VD-OPh reduced HPK1 cleavage and enhanced DCS-induced differentiation of 40AF cells. The results indicate that FL-HPK1 is a positive regulator of vitamin D-induced differentiation in AML cells, but the cleaved HPK1 fragment inhibits differentiation. Thus, high HPK1 cleavage activity contributes to vitamin D resistance, and HPK1 has a dual role in AML cell differentiation.
Authors:
Xiangwen Chen-Deutsch; George P Studzinski
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-04-01
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-04-20     Completed Date:  2013-01-04     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1364-73     Citation Subset:  IM    
Affiliation:
Department of Pathology and Laboratory Medicine, UMDNJ-New Jersey Medical School, Newark, NJ, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Chloromethyl Ketones / pharmacology
Cell Cycle Checkpoints / drug effects*
Cell Differentiation*
Cell Line, Tumor
Diterpenes, Abietane / pharmacology
Drug Resistance, Neoplasm
HL-60 Cells
Humans
Imidazoles / pharmacology
Leukemia, Myeloid, Acute / pathology*
Plant Extracts / pharmacology
Protein-Serine-Threonine Kinases / genetics,  metabolism*
Pyridines / pharmacology
Quinolines / pharmacology
RNA Interference
RNA, Messenger / genetics,  metabolism
RNA, Small Interfering
U937 Cells
Vitamin D / analogs & derivatives*,  metabolism,  pharmacology,  therapeutic use
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Grant Support
ID/Acronym/Agency:
2R01-044722-21//PHS HHS
Chemical
Reg. No./Substance:
0/4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; 0/Amino Acid Chloromethyl Ketones; 0/Diterpenes, Abietane; 0/Imidazoles; 0/Plant Extracts; 0/Pyridines; 0/Quinolines; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/dihydroxy-vitamin D3; 0/quinoline-val-asp(OMe)-CH2-OPH; 1406-16-2/Vitamin D; EC 2.7.1.11/hematopoietic progenitor kinase 1; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; LI791SXT24/salvin
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