Jab1 is a multifunctional protein associated with the signaling pathway, cellcycle regulation, and development, and acts as a key subunit of COP9 signalosome (CSN). Jab1 promotes degradation of the cyclin-dependent kinase inhibitor p27 Kip1 IntroductionThe signals triggered by oncogenic protein kinases ultimately control the cell-cycle machinery to promote cell proliferation via constitutive activation of downstream pathways. However, little is known about how oncogenic signals reach cell-cycle regulators and override the restrictions that suppress undesirable cell proliferation. Bcr-Abl is a cytoplasmic chimeric oncoprotein produced by Philadelphia chromosome translocation and found in more than 90% of patients with chronic myelogenous leukemia (CML). The constitutive tyrosine kinase activity of Bcr-Abl confers growth factor independency and transforming activity to hematopoietic cells in vitro. 1,2 Bcr-Abl activates multiple signaling cascades including the Ras/mitogen-activated protein kinase (MAPK), phosphatidylinositol 3 kinase (PI3K)/Akt, Janus kinase (Jak)/signal transducer and activator of transcription (Stat), and Myc pathways, which are required for mitogen-activated cell proliferation, cell survival, and stress responses. Clinical studies and animal models prove that Bcr-Abl expression serves as the initiating event in the transformation by activating these pathways. [3][4][5] However, downstream elements of the signaling pathways leading to the cell-cycle machinery are poorly understood.The proliferation of mammalian cells is strictly controlled by both negative and positive regulators that specifically function during the G1 phase of the cell-cycle. 6 Among G1 regulators, the cyclin-dependent kinase inhibitor p27 Kip1 is a key component in growth control in response to extracellular signals. 7 Although mutations in the p27 gene are rare in human tumors, reduced expression of the p27 protein correlates well with both histologic aggressiveness and poor prognosis in approximately half of all human cancers. [8][9][10] These low levels of p27 result from increased 26S proteasome-mediated proteolysis. In fact, overexpression of Skp2, a Skp1-Cullin-F-box (SCF) ubiquitin ligase required for degradation of p27, inversely correlates with the reduced level of p27 in several human cancers. 11,12 Recent studies have shown that inhibition of the nuclear import of p27 by protein kinase B (PKB)/Akt-mediated phosphorylation is linked to a poor prognosis in breast cancer. [13][14][15] These results indicate that both accelerated degradation of p27 and the segregation of p27 from the nucleus to the cytoplasm are essential in tumorigenesis. In the case of CML, Bcr-Abl is reported to down-regulate the intracellular level of p27 or to inactivate p27 by cytoplasmic segregation. [16][17][18][19] It is possible that other signaling pathways involved in oncogenesis target the machinery that controls the stability and localization of p27.We previously found that Jab1 promotes p27 degradation by transporting it from the nuc...
By means of the multiple marker analysis, a total of 55 human leukemia-lymphoma cell lines which included 15 T-cell, 30 B-cell, four myelomonocytic-cell, and six non-T, non-B cell lines was characterized for their marker profiles. The multiple markers used included a number of cell surface markers as detected by either rosette or immunofluorescence tests, enzyme assays, cytogenetic analysis, and certain functional assay. Based on the criteria previously defined it was found that all the cell lines were proved to represent original leukemia-lymphoma of ALL, AML, CLL, CML in blastic phase or variety of lymphomas. The monoclonality, a "frozen" state at a specific state of differentiation-maturation, and cytogenetic marker in each leukemia-lymphoma cell line were remarkable common properties and were stable for years of cultivation. Similar, if not identical, general characteristics were observed in the study on 344 cases of uncultured fresh leukemia-lymphomas by the multiple marker analysis. While no single marker specific to any type of tumor was found, the study offers not only a basis for better understanding of the biology of leukemia-lymphoma but also an insight into normal hematopoietic cell differentiation in man.
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