Death associated protein kinase: from regulation of apoptosis to tumor suppressive functions and B cell malignancies.
Death associated protein kinase (DAP-kinase) is a pro-apoptotic calcium/calmodulin-regulated serine/threonine kinase with a multidomain structure that participates in a wide array of apoptotic systems initiated by IFN-gamma, TNF-alpha, activated Fas, and detachment from extracellular matrix. At various stages during tumor development, cells are subjected to apoptosis inducing stimuli and genetic mutations causing inhibition of apoptosis confer a selective advantage to cells. Thus, apoptosis and its regulation play an important role in tumor initiation, progression and metastasis. It has been demonstrated that the tumor-suppressive properties of DAP-kinase operate at two different apoptotic checkpoints in the course of tumor development; first, during the early oncogene-activated apoptotic checkpoint mediated by p19ARF-p53 pathway and second, during the late stages of metastasizing cells entering the circulation after detachment from extracellular matrix. Promoter hypermethylation of DAP-kinase has been observed in a high variety of primary tumors including head and neck tumors, and non-small cell lung cancers, where an association with poor prognosis was also noted. Notably, high frequencies of DAP-kinase methylation have been found in B cell lymphomas and myeloma, where loss of control of c-Myc induced hyperproliferation from inactivated DAP-kinase may possibly play an important role in the pathogenesis of these B cell neoplasms.
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Hematology Section, Department of Anatomical & Cellular Pathology, CUHK, Prince of Wales Hospital, Shatin, HKSAR, People's Republic of China. margaretng@cuhk.edu.hk
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D004789:Enzyme Activation; D019337:Hematologic Neoplasms / Q000378:metabolism*; D006410:Hematopoiesis; D006801:Humans; D007107:Immune System / Q000502:physiology; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D009369:Neoplasms / Q000503:physiopathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases