All-trans retinoic acid induces p62DOK1 and p56DOK2 expression which enhances induced differentiation and G0 arrest of HL-60 leukemia cells.
p62(DOK1) (DOK1) and p56(DOK2) (DOK2) are sequence homologs that act as docking proteins downstream of receptor or nonreceptor tyrosine kinases. Originally identified in chronic myelogenous leukemia cells as a highly phosphorylated substrate for the chimeric p210(bcr-abl) protein, DOK1 was suspected to play a role in leukemogenesis. However, p62(DOK1-/-) fibroblast knockout cells were found to have enhanced MAPK signaling and proliferation due to growth factors, suggesting negative regulatory capabilities for DOK1. The role of DOK1 and DOK2 in leukemogeneis thus is enigmatic. The data in this report show that both the DOK1 and the DOK2 adaptor proteins are constitutively expressed in the myelomonoblastic leukemia cell line, HL-60, and that expression of both proteins is induced by the chemotherapeutic differentiation causing agents, all-trans retinoic acid (atRA) and 1,25-dihydroxyvitamin D3 (VD3). Ectopic expression of either protein enhances atRA- or VD3-induced growth arrest, differentiation, and G(0)/G(1) cell cycle arrest and results in increased ERK1/2 phosphorylation. DOK1 and DOK2 are similarly effective in these capabilities. The data provide evidence that DOK1 and DOK2 proteins have a similar role in regulating cell proliferation and differentiation and are positive regulators of the MAPK signaling pathway in this context.
Lamkin
Thomas J
TJ
Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853, USA.
Chin
Vivian
V
Yen
Andrew
A
D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry / Q000379:methods; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects* / Q000235:genetics; D018922:HL-60 Cells; D006801:Humans; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D010641:Phenotype; D010750:Phosphoproteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology*
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; C115089:DOK2 protein, human; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D014212:Tretinoin; D020929:Mitogen-Activated Protein Kinase Kinases; D002117:Calcitriol