Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human T-cell leukemia virus type I (HTLV-I) has been etiologically associated with the development of the adult T-cell leukemia (ATL) as well as degenerative neurologic syndrome termed tropical spastic paraparesis (TSP). HTLV-I encodes a potent transactivator protein termed Tax that appears to play an important role in the process of T-cell immortalization. Even though the mechanisms by which Tax induces transformation are still unknown, it seems likely that the ability of Tax to alter the expression of many cellular genes plays an important part in this process. Tax does not bind directly to DNA but rather deregulates the activity of cellular transcription factors. One family of host transcription factors whose activity is altered by Tax includes NF-kappa B/Rel. These transcription factors are post-transcriptionally regulated by their assembly with a second family of inhibitory proteins termed I kappa B that serve to sequester the NF-kappa B/Rel complexes in the cytoplasm. Upon cellular activation, I kappa B alpha is phosphorylated, polyubiquitinated, and degraded in the proteasome. This proteolytic event liberates NF-kappa B, permitting its rapid translocation into the nucleus where it binds to its cognate enhancer elements. Similarly, the p105 precursor of the NF-kappa B p50 subunit is also post-translationally processed in the proteasome. The mechanisms by which Tax activates NF-kappa B remain unclear, and findings presented in the literature are often controversial. We identified a physical interaction between Tax and the HsN3 subunit of the human proteasome. This raises the intriguing possibility that physical association of the HsN3 proteasome subunit with HTLV-I Tax coupled with the independent interaction of Tax with either p100 or p65-I kappa B alpha targets these cytoplasmic NF-kappa B/Rel complexes to the proteasome for processing.
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PMID:Interaction of HTLV-I Tax with the human proteasome: implications for NF-kappa B induction. 879 8

The transcription factor NF-kappaB plays an important role in the regulated expression of cytokines in human monocytes. A p100 subunit of NF-kappaB has IkappaB-like properties by sequestering the p65 transactivating subunit in the cytosol of cells. In transient transfection assays we demonstrated that p100 has an inhibitory effect on the NF-kappaB-dependent IL-6 promoter activity. In view of this finding, we studied the regulation of the p100 subunit in human monocytes in response to LPS, the inflammatory cytokines IL-1beta and TNF-alpha and lymphokines. The results demonstrate that LPS, IL-1beta, and TNF-alpha induce p100 expression at mRNA and protein level while IFN-gamma, IL-3 and IL-4/IL-10 have no effect. The induction of p100 expression was shown to be mediated by a two-fold increase in the p100 transcription rate and a two-fold increase in p100 mRNA stability. Furthermore the p100 mediated upregulation was dependent on a tyrosine kinase dependent pathway rather than the protein kinase C pathway. NF-kappaB is a complex of either p50 homodimers or a p50/p65 heterodimer. The latter is known to strongly autoregulate p100 transcription. We therefore examined the composition of NF-kappaB induced by LPS vs the different lymphokines. LPS-induced NF-kappaB showed a distinct p65 supershift whereas the composition of NF-kappaB induced by different lymphokines did not show a change in p65. We conclude that the p100 subunit of the transcription factor NF-kappaB is induced by different inflammatory mediators while lymphokines fail to induce p100 expression which may be caused by the induction of NF-kappaB predominantly consisting of p50 homodimers.
Leukemia 1998 Mar
PMID:Regulation of p100 (NFKB2) expression in human monocytes in response to inflammatory mediators and lymphokines. 952 31

The protein, p100, was previously identified as a G-protein related protein that cycles on and off the cytoplasmic face of the endosome membrane (Traub et al., Biochem. J. 280 (1991) 171-178). Here we present evidence that the inositol polyphosphates, inositol 1,4, 5-trisphosphate (IP3) and inositol hexakisphosphate (IP6), release p100 from light-density microsomal membranes and inhibit rebinding of p100 through receptors, which are specific for IP3 or for IP6. These receptors can be co-extracted with p100 from the microsomes by 0.5 M Tris-HCl and, in the soluble state, they exhibit similar binding activity towards the inositol polyphosphates as do untreated microsomes. Soluble p100 self-aggregates and this aggregation is blocked by both IP3 and IP6. Stimulation of permeabilized rat basophilic leukemia (RBL-2H3) cells with carbachol, via transfected muscarinic m1 receptors, results in increased levels of inositol polyphosphates and the quantitative release of p100 into the cytosol. This effect is reversible and cytosolic p100 rebinds to the membrane as the levels of inositol polyphosphates decline. These findings suggest that p100 may belong to a family of IP-binding proteins whose intracellular localization is determined by extracellular signals.
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PMID:Inositol polyphosphates regulate the membrane interactions of the endosomal p100, G-protein-related protein. 976 43

The hematopoietic cell S/T kinase Pim-1 was originally discovered as a target of murine leukemia provirus integration, and when expressed at increased levels is predisposing to lymphomagenesis. Recently, Pim-1 has been shown to enhance the activities of p100, c-Myb and cdc25a, and in part this might explain reported effects on mitogenesis. In the context of cytokine withdrawal, Pim-1 also can attenuate programmed cell death (PCD). Cytokine withdrawal, however, alters signaling pathways and can complicate the dissection of mitogenic vs apoptotic responses. To better study possible effects of Pim-1 on PCD, a hematopoietic cell model was developed in which proliferation was supported efficiently by SCF plus EPO in the absence of endogenous Pim-1 gene expression. This was provided by factor-dependent FDCW2 cells that express endogenous and functional c-Kit, and were transfected stably with truncated Epo receptor form mutated at a Y343 STAT5 binding site. In proliferating cells, exogenously expressed Pim-1 was observed to efficiently inhibit PCD as induced by either Co60 or adriamycin, and the dose-dependent nature of this effect was established in several independent clones. By comparison, effects of exogenous Pim-1 on mitogenesis were nominal. In addition, in cell fractionation studies an estimated 25% of Mr 34000 Pim-1 (but not Mr 44000 Pim-1) was present in nuclear extracts. Thus, Pim-1 efficiently buffers hematopoietic progenitor cells against death as induced by several clinically important apoptotic agents, and may directly target nuclear effectors.
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PMID:Pim-1 kinase protects hematopoietic FDC cells from genotoxin-induced death. 1095 75

IkappaB kinase (IKK) is a key mediator of NF-kappaB activation induced by various immunological signals. In T cells and most other cell types, the primary target of IKK is a labile inhibitor of NF-kappaB, IkappaBalpha, which is responsible for the canonical NF-kappaB activation. Here, we show that in T cells infected with the human T-cell leukemia virus (HTLV), IKKalpha is targeted to a novel signaling pathway that mediates processing of the nfkappab2 precursor protein p100, resulting in active production of the NF-kappaB subunit, p52. This pathogenic action is mediated by the HTLV-encoded oncoprotein Tax, which appears to act by physically recruiting IKKalpha to p100, triggering phosphorylation-dependent ubiquitylation and processing of p100. These findings suggest a novel mechanism by which Tax modulates the NF-kappaB signaling pathway.
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PMID:Retroviral oncoprotein Tax induces processing of NF-kappaB2/p100 in T cells: evidence for the involvement of IKKalpha. 1172 16

The NF-kappaB2/p100 and bcl-3 genes are involved in chromosomal translocations described in chronic lymphocytic leukemias (CLL) and non-Hodgkin's lymphomas, and nuclear factor kappaB (NF-kappaB) protects cancer cells against apoptosis. Therefore, we investigated whether this transcription factor could modulate the expression of the Bcl-2 antiapoptotic protein. Bcl-2 promoter analysis showed multiple putative NF-kappaB binding sites. Transfection assays of bcl-2 promoter constructs in HCT116 cells showed that NF-kappaB can indeed transactivate bcl-2. We identified a kappaB site located at position -180 that can only be bound and transactivated by p50 or p52 homodimers. As p50 and p52 homodimers are devoid of any transactivating domains, we showed that they can transactivate the bcl-2 promoter through association with Bcl-3. We also observed that stable overexpression of p100 and its processed product p52 can induce endogenous Bcl-2 expression in MCF7AZ breast cancer cells. Finally, we demonstrated that, in breast cancer and leukemic cells (CLL), high NF-kappaB2/p100 expression was associated with high Bcl-2 expression. Our data suggest that Bcl-2 could be an in vivo target gene for NF-kappaB2/p100.
Leukemia 2003 Jul
PMID:NF- kappa B2/p100 induces Bcl-2 expression. 1283 24

Processing of the nf-kappab2 gene product p100 to generate p52 is a tightly regulated event, consistent with the fact that the processing product, p52, is hardly detected in most cell types, including T cells, although the precursor p100 is expressed abundantly in these cells. However, in T cells transformed by the human T-cell leukemia virus type I (HTLV-I), p100 processing is very active, resulting in high level expression of p52. Because overproduction of p52 is associated with lymphoid hyperplasia and transformation, deregulation of p100 processing may be part of the oncogenic mechanism of HTLV-I. We demonstrated previously that HTLV-I Tax oncoprotein is a potent inducer of p100 processing through specific targeting of IKKalpha via IKKgamma to p100 to trigger p100 phosphorylation and ubiquitination. In this study, we further show that Tax-mediated recruitment of IKKalpha to p100 requires serines 866 and 870 of p100, shown to be essential for inducible processing of p100. Upon interaction with p100, activated IKKalpha phosphorylates both N- and C-terminal serines of p100 (serines 99, 108, 115, 123 and 872), serving as a critical step in Tax-induced p100 processing. Using a genetic approach, we find that beta-transducin repeat-containing protein, a component of the SCF ubiquitin ligase complex, previously shown to be required for physiological p100 processing mediated by nuclear factor-kappaB-inducing kinase, is only partially involved in Tax-induced processing of p100. These results indicate that both beta-transducin repeat-containing protein-dependent and -independent mechanisms contribute to Tax-deregulated p100 processing, further suggesting the involvement of different mechanisms in cellular and viral pathways of p100 processing.
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PMID:Tax deregulation of NF-kappaB2 p100 processing involves both beta-TrCP-dependent and -independent mechanisms. 1531 Jul 58

Processing of NF-kappa B2 precursor protein p100 to generate p52 is tightly regulated. However, this proteolytic event could be actively induced by the NF-kappa B-inducing kinase and the human T-cell leukemia virus-encoded oncoprotein Tax or be constitutively turned on due to the loss of the C-terminal portion of p100. Whereas NF-kappa B-inducing kinase-mediated p100 processing requires beta-transducin repeat-containing protein, constitutive processing of p100 is independent of this protein. On the other hand, Tax-induced processing of p100 appears to be both beta-transducin repeat-containing protein-dependent and -independent. We show here that, besides the C-terminal sequences, multiple functional regions, including the two alpha-helices, dimerization domain, nuclear localization sequence, and glycine-rich region, located in the N terminus of p100, also play important roles in both constitutive and inducible processing, suggesting a common mechanism for p100 processing. We further demonstrate that with the help of the C-terminal death domain and I kappa B kinase alpha-targeting serines, the C-terminal ankyrin-repeat domain of p100 strongly interacts with its N-terminal dimerization domain and nuclear localization sequence, thereby bringing the C- and N-terminal sequences together to form a three-dimensional domain. This presumptive domain is not only responsible for suppression of constitutive processing but also required for inducible processing of p100. Taken together, these studies highlight the mechanism by which the different sequences within p100 work in concert to regulate its processing and shed light on the mechanisms of how p100 processing is tightly and delicately controlled.
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PMID:Regulation of NF-kappa B2 p100 processing by its cis-acting domain. 1548 30

Of the cell cycle-associated genes regulated by human T-cell leukemia virus type-1 (HTLV-1) Tax, cyclin-dependent kinase (CDK) inhibitor p21WAF1 is upregulated in HTLV-1-infected cells. Previously, we reported that p21WAF1 stimulated Tax-dependent NF-kappaB activation which influences a variety of cellular processes, including proliferation, differentiation, and apoptosis. In HTLV-1-infected cells, Tax is primarily involved in the constitutive activation of NF-kappaB signaling. Here, we demonstrate that p21WAF1 affects Tax-dependent NF-kappaB signaling by inducing p100/52, an NF-kappaB-related protein. W4, a Tax-transformed rat fibroblast cell line, exhibits the constitutive activation of NF-kappaB signaling, potentially mediated by overexpression of RelB. Ectopic expression of p21WAF1 in W4 cells, which lack endogenous expression due to methylation of the p21WAF1 promoter, induces the expression of p100/52. Bcl-2 expression was also upregulated by ectopic p21WAF1 in this cell line, suggesting that p21WAF1 plays an important role in the regulation of apoptosis by modulating NF-kappaB signaling in Tax-expressing rat fibroblasts. We also address the expression of NF-kappaB-related proteins in HTLV-1-infected cells.
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PMID:p21WAF1 modulates NF-kappaB signaling and induces anti-apoptotic protein Bcl-2 in Tax-expressing rat fibroblast. 1566 Nov 57

Processing of NF-kappaB2 precursor protein p100 to generate p52 is tightly controlled, which is important for proper function of NF-kappaB. Accordingly, constitutive processing of p100, caused by the loss of its C-terminal processing inhibitory domain due to nfkappab2 gene rearrangements, is associated with the development of various lymphomas and leukemia. In contrast to the physiological processing of p100 triggered by NF-kappaB-inducing kinase (NIK) and its downstream kinase, IkappaB kinase alpha (IKKalpha), which requires the E3 ligase, beta-transducin repeat-containing protein (beta-TrCP), and occurs only in the cytoplasm, the constitutive processing of p100 is independent of beta-TrCP but rather is regulated by the nuclear shuttling of p100. Here, we show that constitutive processing of p100 also requires IKKalpha, but not IKKbeta (IkappaB kinase beta) or IKKgamma (IkappaB kinase gamma). It seems that NIK is also dispensable for this pathogenic processing of p100. These results demonstrate a general role of IKKalpha in p100 processing under both physiological and pathogenic conditions. Additionally, we find that IKKalpha is not required for the nuclear translocation of p100. Thus, these results also indicate that p100 nuclear translocation is not sufficient for the constitutive processing of p100.
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PMID:Essential role of IkappaB kinase alpha in the constitutive processing of NF-kappaB2 p100. 1567 66


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