Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cδ

Ringshausen, Ingo; Schneller, Folker; Bogner, Christian; Hipp, Susanne; Duyster, Justus; Peschel, Christian; Decker, Thomas

doi:10.1182/blood-2002-02-0539

Cited by 230 publications

(241 citation statements)

References 61 publications

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“…Previous work, on cells other than CLLs, indicated that 4HPR promotes Mcl-1 downregulation through PKCdelta cleavage and activation. 30,31 However, PKCdelta was already active in our untreated CLLs, in accordance with previous work demonstrating constitutive activation of PKCdelta in CLL cells 40,41 and antiapoptotic, instead of death-promoting, activity in these cells. 41,42 Altogether, different from other cell systems, in CLL cells PKCdelta appeared not to participate in 4HPR apoptosis or Mcl-1 downregulation.…”

Section: Discussionsupporting

confidence: 92%

N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity

et al. 2012

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Section: Discussionsupporting

confidence: 92%

N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity

et al. 2012

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“…Furthermore, we uncovered that the protein kinase C-d (PKC-d) is a downstream target of PI3-K and also constitutively activated in CLL cells. 5 Likewise, blockade of PKC-d induces apoptosis in malignant B cells, whereas normal peripheral B cells are unaffected by PKC-d inhibition.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of apoptosis-induction by rottlerin: therapeutic implications for B-CLL

et al. 2006

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Constitutively activated signaling pathways contribute to the apoptosis-defect of B-CLL cells. Protein kinase C-d is a permanently activated kinase and a putative downstream target of phosphatidylinositol-3 kinase in B-CLL. Blockade of protein kinase C-d (PKC-d) by the highly specific inhibitor rottlerin induces apoptosis in chronic lymphocytic leukaemia (CLL) cells. By co-culturing bone marrow stromal and CLL cells, we determined that the proapoptotic effect of rottlerin is not abolished in the presence of survival factors, indicating that a targeted therapy against PKC-d might be a powerful approach for the treatment of CLL patients. The downstream events following rottlerin treatment engage mitochondrial and nonmitochondrial pathways and ultimately activate caspases that execute the apoptotic cell death. Herein we report that the inhibition of PKC-d decreases the expression of the important antiapoptotic proteins Mcl-1 and XIAP accompanied by a loss of the mitochondrial membrane potential Dw. In addition, we discovered that ZAP-70-expressing cells are significantly more susceptible to rottlerin-induced cell death than ZAP-70 negative cells. We finally observed that rottlerin can augment cell toxicity induced by standard chemotherapeutic drugs. Conclusively, PKC-d is a promising new target in the combat against CLL.

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“…[1][2][3] Overexpression of antiapoptotic genes, such as Bcl-2, deficiency of the proapoptotic Fas pathway and sustained activation of Akt and nuclear factor k-B (NF-kB) proteins have been implied in regulating the life of leukaemic B cells. [3][4][5][6] Within the past decade, CLL has been considered as a disease primarily related to the delivery of survival signals from microenvironment to leukaemic cells. 7 Moreover, signalling molecules involved in cell-cycle progression, including extracellular signal-regulated kinase (ERK), c-Jun aminoterminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), were found to be constitutively activated in CLL, [6][7][8] raising the possibility that an altered regulation of cell proliferation might also contribute to the leukaemic process and leading to ask if 'negative' or anti-proliferative signals might be involved as well.…”

Section: Introductionmentioning

confidence: 99%

Lack of the leukocyte-associated Ig-like receptor-1 expression in high-risk chronic lymphocytic leukaemia results in the absence of a negative signal regulating kinase activation and cell division

Poggi¹,

Catellani

Bruzzone

et al. 2008

Leukemia

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In this study, we analysed 30 patients with B-cell chronic lymphocytic leukaemia (CLL), compared with 10 healthy donors, for the expression and function of the leukocyteassociated Ig-like receptor-1 (LAIR-1). LAIR-1 is an inhibitory receptor containing a cytoplasmic tyrosine-based inhibitory motif (ITIM) that binds to the SH2 domain of phosphatases, leading to dephosphorylation of different kinases. Constitutive activation of c-Jun aminoterminal kinase (JNK), p38 mitogenactivated protein kinase and extracellular signal-regulated kinase, has been reported in CLL. We show that LAIR-1 is absent in high-risk (HR) CLL and differently expressed on intermediate-and low-risk CLL and the intensity of expression, which is always significantly lower than in healthy donors, correlates with disease stage and progression. Interestingly, both constitutive and sIgM-induced phosphorylation of p38 and JNK is inhibited by LAIR-1 through an ITIM-dependent signal, as demonstrated by the use of specific ITIM-binding peptides; importantly, this inhibitory signal is missing when LAIR-1 is not expressed as occurs in HR CLL. Moreover, engagement of LAIR-1 blocks constitutive and sIgM-induced Akt phosphorylation, besides nuclear factor j-B nuclear translocation, and prevents CLL division. These results suggest that CLL lacking LAIR-1 may miss one of the molecular mechanisms controlling B-cell activation and proliferation.

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Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cδ

Abstract: In the present study we analyzed the role of phophatidylinositol-3 kinase (PI- 3K

Cited by 230 publications

References 61 publications

N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity

N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity

Mechanisms of apoptosis-induction by rottlerin: therapeutic implications for B-CLL

Lack of the leukocyte-associated Ig-like receptor-1 expression in high-risk chronic lymphocytic leukaemia results in the absence of a negative signal regulating kinase activation and cell division

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