| Tumor suppressor p53 status does not determine the differentiation-associated G₁ cell cycle arrest induced in leukemia cells by 1,25-dihydroxyvitamin D₃ and antioxidants. | |
| | |
MedLine Citation:
|
PMID: 20543580 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Vitamin D derivatives can induce differentiation of human acute myeloid leukemia (AML) cells. Here, we investigated if the G₁ cell cycle block associated with monocytic differentiation is modulated by the p53 status of the cells treated with 1,25D, alone or with plant antioxidants carnosic acid (C) or silibinin (S), and a p38 MAPK inhibitor SB202190 (SB), a combination (D-C/S-SB) previously shown to enhance differentiation of AML p53null cells. D-C/S-SB enhanced differentiation of OCI-AML3 (p53wt) and as expected HL60 (p53 null) cells, but not of MOLM-13 (p53wt) cells. Conversely, MOLM-13 (p53wt) cells treated with 1,25D and/or D-C/S-SB, resembled HL60 (p53 null) cells in rapid G₁ block, while OCI-AML3 (p53wt) cells showed a delayed G₁ block when treated in a similar way, indicating that there is no relationship between the p53 status and G₁ block. Western blot analysis revealed that 1,25D and D-C/S-SB increased the inhibitory phosphorylation levels MEK-1 (P-Thr286), but decreased the levels of activated ERK1/2 (Thr202/Tyr204;Thr185/Tyr187), again without any apparent relationship to the p53 status. Interestingly, the increased levels of p21(Waf1/Cip1) were insufficient to promote a G₁ block in this system, as only cell lines with increased levels of p27(Kip1) and p35Nck5a, an activator of Cdk5, showed a rapid G₁ block. Overall, our data show that the p53-p21 axis is unlikely to have a role in differentiation-associated G₁ block in AML cells with wt p53, and that this block is achieved by several, possibly co-operating but redundant pathways, that include inhibition of MEK-1 by p35Nck5a-activated Cdk5. |
| | |
Authors:
|
Thelma Thompson; Michael Danilenko; Lyubomir Vassilev; George P Studzinski |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-08-13 |
Journal Detail:
|
Title: Cancer biology & therapy Volume: 10 ISSN: 1555-8576 ISO Abbreviation: Cancer Biol. Ther. Publication Date: 2010 Aug |
Date Detail:
|
Created Date: 2010-10-27 Completed Date: 2011-05-05 Revised Date: 2013-02-05 |
Medline Journal Info:
|
Nlm Unique ID: 101137842 Medline TA: Cancer Biol Ther Country: United States |
Other Details:
|
Languages: eng Pagination: 344-50 Citation Subset: IM |
Affiliation:
|
Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Antioxidants
/
pharmacology* Apoptosis / drug effects Blotting, Western Calcitriol / pharmacology* Cell Cycle / drug effects, genetics Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p21 / genetics, metabolism Diterpenes, Abietane / pharmacology Drug Synergism G1 Phase / drug effects*, genetics HL-60 Cells Humans Imidazoles / pharmacology Leukemia, Myeloid, Acute* / genetics, metabolism, pathology Mitogen-Activated Protein Kinase 1 / metabolism Mitogen-Activated Protein Kinase 3 / metabolism Plant Extracts / pharmacology Pyridines / pharmacology Silymarin / pharmacology Tumor Suppressor Protein p53 / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
|
R01 CA044722-21/CA/NCI NIH HHS; R01-CA-117942-3/CA/NCI NIH HHS; R01-CA-44722-20/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; 0/Antioxidants; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Diterpenes, Abietane; 0/Imidazoles; 0/Plant Extracts; 0/Pyridines; 0/Silymarin; 0/Tumor Suppressor Protein p53; 32222-06-3/Calcitriol; 4RKY41TBTF/silybin; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; LI791SXT24/salvin |
| Comments/Corrections | |
Comment In:
|
Cancer Biol Ther. 2010 Aug 15;10(4):351-3
[PMID:
21046823
]
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: DNA methylation in endometrial cancer.
Next Document: The SUMO pathway functions in mouse oocyte maturation.