Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disrupting inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)/B-cell lymphoma 2 (Bcl-2) complexes using a cell-permeable peptide (stabilized TAT-fused IP3R-derived peptide (TAT-IDP(S))) that selectively targets the BH4 domain of Bcl-2 but not that of B-cell lymphoma 2-extra large (Bcl-Xl) potentiated pro-apoptotic Ca(2+) signaling in chronic lymphocytic leukemia cells. However, the molecular mechanisms rendering cancer cells but not normal cells particularly sensitive to disrupting IP3R/Bcl-2 complexes are poorly understood. Therefore, we studied the effect of TAT-IDP(S) in a more heterogeneous Bcl-2-dependent cancer model using a set of 'primed to death' diffuse large B-cell lymphoma (DL-BCL) cell lines containing elevated Bcl-2 levels. We discovered a large heterogeneity in the apoptotic responses of these cells to TAT-IDP(S) with SU-DHL-4 being most sensitive and OCI-LY-1 being most resistant. This sensitivity strongly correlated with the ability of TAT-IDP(S) to promote IP3R-mediated Ca(2+) release. Although total IP3R-expression levels were very similar among SU-DHL-4 and OCI-LY-1, we discovered that the IP3R2-protein level was the highest for SU-DHL-4 and the lowest for OCI-LY-1. Strikingly, TAT-IDP(S)-induced Ca(2+) rise and apoptosis in the different DL-BCL cell lines strongly correlated with their IP3R2-protein level, but not with IP3R1-, IP3R3- or total IP3R-expression levels. Inhibiting or knocking down IP3R2 activity in SU-DHL-4-reduced TAT-IDP(S)-induced apoptosis, which is compatible with its ability to dissociate Bcl-2 from IP3R2 and to promote IP3-induced pro-apoptotic Ca(2+) signaling. Thus, certain chronically activated B-cell lymphoma cells are addicted to high Bcl-2 levels for their survival not only to neutralize pro-apoptotic Bcl-2-family members but also to suppress IP3R hyperactivity. In particular, cancer cells expressing high levels of IP3R2 are addicted to IP3R/Bcl-2 complex formation and disruption of these complexes using peptide tools results in pro-apoptotic Ca(2+) signaling and cell death.
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PMID:IP3R2 levels dictate the apoptotic sensitivity of diffuse large B-cell lymphoma cells to an IP3R-derived peptide targeting the BH4 domain of Bcl-2. 2368 Dec 27

Reference treatment of advanced prostate cancer (PCa) relies on pharmacological or surgical androgen deprivation therapy. However, it is only temporarily efficient as tumor cells inevitably adapt to the low testosterone environment and become hormone-refractory (HRPCa). We observed that androgen removal in HRPCa-derived LNCaP cells causes different alterations in their Ca(2+) homeostasis among which a reduction of ER Ca(2+) content. We show that the decrease in [Ca(2+)]ER is due to a modest overexpression of type 1 IP3R and a threefold increased phosphorylation of IP3R1 on Ser-1716, a protein kinase A (PKA) consensus site, both implicated in ER Ca(2+) leak. Accordingly, ER Ca(2+) content was restored by siRNA-mediated down-regulation of IP3R1 or by inhibition of its phosphorylation by competition with a permeant TAT-peptide containing the Ser-1716 consensus phosphorylation sequence or by treatment with the PKA inhibitor H89. Moreover, inhibition of the IP3R1 phosphorylation by both methods sensitized the LNCaP cells to androgen deprivation-induced apoptosis. In addition, SERCA2b overexpression precluded the effect of androgen deprivation on ER Ca(2+) store content and reduced resistance to androgen deprivation. Taken together, these results indicate that lowering the ER Ca(2+)-store content by increasing IP3R1 levels and IP3R1 phosphorylation by PKA is a protective mechanism by which HRPCa-derived cells escape cell death in the absence of androgenic stimulation.
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PMID:Endoplasmic reticulum Ca(2+) content decrease by PKA-dependent hyperphosphorylation of type 1 IP3 receptor contributes to prostate cancer cell resistance to androgen deprivation. 2574 Apr 20