CD5 provides viability signals to B cells from a subset of B-CLL patients by a mechanism that involves PKC

Pérez-Chacón, Gema; Vargas, Juan A.; Zurdo, Julia; Morado, Marta; Rosado, Silvia; Martín-Donaire, Trinidad; Losada-Fernandez, Ignacio; Rebolleda, Nerea; Pérez-Aciego, Paloma

doi:10.1016/j.leukres.2006.03.021

Cited by 22 publications

(24 citation statements)

References 76 publications

(106 reference statements)

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“…CD5 and the BCR colocalization in lipid rafts may be necessary for the early signaling events leading to apoptosis . Similar pattern of survival and apoptosis responses following anti-CD5 stimulation were obtained in the study of PerezChacon and collaborators (Perez-Chacon et al, 2007). Moreover, authors showed that in unstimulated and resting CD5 transfected B cells, it was observed that CD5 + B cells produce more IL-10 than CD5 -B cells enhancing survival of B cells , Garaud et al, 2011.…”

Section: Calcium Signaling and Chronic Lymphocytic Leukemia 383supporting

confidence: 72%

Calcium signaling and cell fate: how can Ca2+ signals contribute to wrong decisions for Chronic Lymphocytic Leukemic B lymphocyte outcome?

Debant

Hémon²,

Brigaudeau³

et al. 2015

Int. J. Dev. Biol.

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Ca2+ signaling is a key regulator of B lymphocyte cell fate and defects in this signaling pathway have been reported in numerous diseases such as Chronic lymphocytic leukemia (CLL). CLL is a B cell clonal disorder characterized by the accumulation of mature monoclonal CD5 + B cells. Although CLL could be considered to be a proliferative disease, most circulating CLL B cells are arrested in the G0 phase of the cell cycle and present both defects in calcium (Ca 2+ ) homeostasis and signaling. The Ca 2+ response to antigen ligation is heterogeneous and related, in part, to defects arising from the incapacity to respond to B cell receptor (BCR) engagement (anergy), to the expression of T cell kinases (e.g. Zap70), and to the presence of negative feedback regulation by phosphatases (e.g. SHP-1). Anergic CD5 + CLL B cells are characterized by an elevated basal Ca 2+ level, IgM/CD79 downregulation, a constitutive activation of BCR pathway kinases, and an activation of the nuclear factor of activated T cells (NF-AT). Based on the Ca2+ response, patients are classified into three groups: unresponders, responders with apoptosis, and responders with entry in the cell cycle. Moreover, internal and direct interaction between leukemic BCR-HCDR3 epitopes at the plasma membrane and interaction between Bcl-2 and the IP3-receptor at the endoplasmic reticulum are also suspected to interfere with the intracellular Ca 2+ homeostasis in CLL-B cells. As a whole, the Ca 2+ pathway is emerging to play a key role in malignant CLL-B survival, disease progression, and last but not least, in the therapeutic response.

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Section: Calcium Signaling and Chronic Lymphocytic Leukemia 383supporting

confidence: 72%

Calcium signaling and cell fate: how can Ca2+ signals contribute to wrong decisions for Chronic Lymphocytic Leukemic B lymphocyte outcome?

Debant

Hémon²,

Brigaudeau³

et al. 2015

Int. J. Dev. Biol.

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“…Natural phosphorylation of regulatory tyrosines on CD5 in CLL B cells reflects chronic activation (18), and sustained signaling through the BCR promotes further expression of CD5 (37). Thus, BCR engagement favors the expression of CD5 (38) which provides viability signals for B cells in a subset of CLL patients (39,40). The prediction from these results is that chronic activation of malignant B cells (17) results in their protection from apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Selection of the Alternative Exon 1 from thecd5Gene Down-Regulates Membrane Level of the Protein in B Lymphocytes

Garaud¹,

Dantec²,

Berthou³

et al. 2008

The Journal of Immunology

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The human cd5 gene has two alternative exons 1: exon 1A (E1A) which encodes the full-length (FL) CD5 protein and exon 1B (E1B) which encodes a truncated (TR) isoform. The FL variant of CD5 protein is translocated to the plasma membrane, while its TR variant is retained in the cytoplasm. Because there is an inverse relationship between the levels of FL-CD5 and TR-CD5 in B cells, we have addressed the issue of how the selection of exon 1 is determined. In leukemic B cells, DNA methyltransferase (DNMT)1-induced methylation of E1B prevents its transcription. Furthermore, the level of mRNA for DNMT1 correlates inversely with that of mRNA for CD5-E1B. However, suppression of E1B transcription is incomplete, and some molecules of TR-CD5 continue to be synthesized. Bortezomid-induced inhibition of the proteasome establishes that these TR-CD5 molecules are cleared through the ubiquitin-proteasome pathway. Transfection of CD5 mutants into COS-1 cells locates the ubiquitin-binding site at the second destruction box of the extracellular region of CD5. Activation of the B cells by anti-IgM, Staphylococcus aureus Cowan I (SAC), or PMA up-regulates DNMT1, and thereby CD5-E1A mRNA at the expense of CD5-E1B mRNA. Aberrant synthesis of TR-CD5 is thus offset by balanced degradation of excessive protein. Dysregulation of these mechanisms reduces the expression level of membrane CD5, and thereby diminishes the threshold of the response by cells expressing CD5.

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“…In general, PKC activator-mediated alterations in Bcl-2 were associated with protection/resistance from spontaneous or stimulus-induced apoptosis in a variety of cells, including B-CLL cells [123,124], rat cardiomyocytes [125] and GT1-7 neuronal cells [126]. In contrast, there is some evidence that PKC can enhance drug-induced apoptosis by increasing the expression of BAD [127] or by inhibiting the expression of Bcl-2 [128].…”

Section: Pkcε and Bcl-2 Family: Many Partners In The Dance Of Deathmentioning

confidence: 99%

Protein kinase Cε makes the life and death decision

Basu

Sivaprasad

2007

Cellular Signalling

144

154

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Cancer is caused by dysregulation in cellular signaling systems that control cell proliferation, differentiation and cell death. Protein kinase C (PKC), a family of serine/threonine kinases, plays an important role in the growth factor signal transduction pathway. PKCε, however, is the only PKC isozyme that has been considered as an oncogene. It can contribute to malignancy by enhancing cell proliferation or by inhibiting cell death. This review focuses on how PKCε collaborates with other signaling pathways, such as Ras/Raf/ERK and Akt, to regulate cell survival and cell death. We have also discussed how PKCε mediates is antiapoptotic signal by altering the level or function of proand antiapoptotic Bcl-2 family members.

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CD5 provides viability signals to B cells from a subset of B-CLL patients by a mechanism that involves PKC

Cited by 22 publications

References 76 publications

Calcium signaling and cell fate: how can Ca2+ signals contribute to wrong decisions for Chronic Lymphocytic Leukemic B lymphocyte outcome?

Calcium signaling and cell fate: how can Ca2+ signals contribute to wrong decisions for Chronic Lymphocytic Leukemic B lymphocyte outcome?

Selection of the Alternative Exon 1 from thecd5Gene Down-Regulates Membrane Level of the Protein in B Lymphocytes

Protein kinase Cε makes the life and death decision

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