Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic myelogenous leukemia (CML) is a disease characterized by the presence of p210(bcr-abl), a chimeric protein with tyrosine kinase activity. Substrates for p210(bcr-abl) are likely to be involved in the pathogenesis of CML. Here we describe the purification, cDNA cloning, and characterization of a 56-kDa tyrosine phosphorylated protein, p56(dok-2) (Dok-2), from p210(bcr-abl) expressing cells. The human dok-2 cDNA encodes a 412-amino acid protein with a predicted N-terminal pleckstrin homology domain as well as several other features of a signaling molecule, including 13 potential tyrosine phosphorylation sites, six PXXP motifs, and the ability to bind to p120(RasGAP). Dok-2 was shown to be 35% identical to p62(dok-1), a recently identified RasGAP binding protein from CML cells, and analysis of the expressed sequence tag data base revealed the presence of at least four additional proteins containing a Dok homology sequence motif. Dok mRNAs were primarily expressed in tissues of hematopoietic origin. These findings strongly suggest that a family of Dok-related proteins exists that bind to RasGAP and may mediate the effects of p210(bcr-abl) in CML.
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PMID:Molecular cloning and characterization of p56dok-2 defines a new family of RasGAP-binding proteins. 947 21

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.
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PMID:All-trans retinoic acid induces p62DOK1 and p56DOK2 expression which enhances induced differentiation and G0 arrest of HL-60 leukemia cells. 1682 27