G paclitaxel-induced mitotic arrest, Bcl-2 was phosphorylated and more tightly bound

G paclitaxel-induced mitotic arrest, Bcl-2 was phosphorylated and more tightly bound to Bak and Bim. Collectively, these results suggest that phosphorylation of the Bcl-2 FLD leads to a conformational change in the “Bcl-2 core” that affects binding of pro-apoptotic proteins to the BH3 binding groove.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptBiochim Biophys Acta. Author manuscript; available in PMC 2016 July 01.Correia et al.PageInterpretation of these results would have been enhanced by structural information about the impact of FLD alterations on overall Bcl-2 conformation. Unfortunately, all published Bcl-2 structures either lack the FLD or replace it with the corresponding region of Bcl-xL [148, 149]. Phosphorylation also modulates the function of other anti-apoptotic Bcl-2 family members. Bcl-xL is phosphorylated on T47 and S62 [150]. Phosphorylation of the latter site by JNK decreases binding of Bcl-xL to Bax, thus diminishing Bcl-xL anti-apoptotic function [151]. Likewise, Mcl-1 phosphorylation at S159 by glycogen synthase kinase-3 (GSK-3) diminishes Mcl-1 anti-apoptotic function, in this case by enhancing Mcl-1 binding to the LCZ696MedChemExpress LCZ696 ubiquitin E3 ligase TrCP [152] and subsequent turnover [153]. In contrast, CDK- and JNKmediated Mcl-1 phosphorylation at S64 increases Mcl-1 binding to Noxa, Bak and Bim, thereby potentiating its anti-apoptotic activity [154]. Because phosphorylation of Bcl-2 (on its FLD) and Mcl-1 (at S64) increases the anti-apoptotic effects of these proteins, it has been suggested that these phosphorylations might contribute to chemoresistance [155?57].Author Manuscript Author Manuscript Author Manuscript Author Manuscript3. BCL2 sequence variation3.1. BCL2 sequence variation in clinical lymphomas As indicated above, BCL2 translocation to the IGH locus contributes to high level Bcl-2 expression in 90 of FLs and 20 of de novo diffuse large B-cell lymphomas (DLBCLs), mostly of the germinal center B-cell subtype (GCB-DLBCL) [158]. Some of these lymphomas also contain BCL2 mutations. Single nucleotide variants (SNVs), including some that cause amino acid substitutions and others that are silent, were demonstrated soon after BCL2 was cloned [159, 160]. Detection of similar SNVs in untreated FL ruled out chemotherapy as a cause of these BCL2 Procyanidin B1 site mutations [159]. In contrast to the impact of other abnormalities involving BCL2, e.g., the extremely poor prognosis of so-called “double hit” lymphomas that harbor translocations involving both the MYC and BCL2 genes [161], the effects of BCL2 SNVs on DLBCL and FL have been less clear. Recent sequencing of large numbers of primary DLBCL samples and matched germline DNA has demonstrated a high incidence of tumor-associated BCL2 mutations and linked these changes to somatic hypermutation, an activation-induced cytidine deaminase- (AID-) driven mutagenic process that ordinarily generates antibody diversity [162?65]. Because most BCL2 mutations in DLBCL (60?0 ) are synonymous [162] and not associated with any impact on chemosensitivity or survival [165], it has been assumed that BCL2 mutations in DLBCL are passenger mutations. Additional studies have examined BCL2 mutations in FL. More indolent than DLBCL, FL nonetheless carries a 2? /year risk of transformation to a more aggressive neoplasm. Transformed FL (tFL) most often resembles DLBCL morphologically [166, 167] but historically has been quite resistant to therapy [167, 168]. This poor therapeutic response of.G paclitaxel-induced mitotic arrest, Bcl-2 was phosphorylated and more tightly bound to Bak and Bim. Collectively, these results suggest that phosphorylation of the Bcl-2 FLD leads to a conformational change in the “Bcl-2 core” that affects binding of pro-apoptotic proteins to the BH3 binding groove.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptBiochim Biophys Acta. Author manuscript; available in PMC 2016 July 01.Correia et al.PageInterpretation of these results would have been enhanced by structural information about the impact of FLD alterations on overall Bcl-2 conformation. Unfortunately, all published Bcl-2 structures either lack the FLD or replace it with the corresponding region of Bcl-xL [148, 149]. Phosphorylation also modulates the function of other anti-apoptotic Bcl-2 family members. Bcl-xL is phosphorylated on T47 and S62 [150]. Phosphorylation of the latter site by JNK decreases binding of Bcl-xL to Bax, thus diminishing Bcl-xL anti-apoptotic function [151]. Likewise, Mcl-1 phosphorylation at S159 by glycogen synthase kinase-3 (GSK-3) diminishes Mcl-1 anti-apoptotic function, in this case by enhancing Mcl-1 binding to the ubiquitin E3 ligase TrCP [152] and subsequent turnover [153]. In contrast, CDK- and JNKmediated Mcl-1 phosphorylation at S64 increases Mcl-1 binding to Noxa, Bak and Bim, thereby potentiating its anti-apoptotic activity [154]. Because phosphorylation of Bcl-2 (on its FLD) and Mcl-1 (at S64) increases the anti-apoptotic effects of these proteins, it has been suggested that these phosphorylations might contribute to chemoresistance [155?57].Author Manuscript Author Manuscript Author Manuscript Author Manuscript3. BCL2 sequence variation3.1. BCL2 sequence variation in clinical lymphomas As indicated above, BCL2 translocation to the IGH locus contributes to high level Bcl-2 expression in 90 of FLs and 20 of de novo diffuse large B-cell lymphomas (DLBCLs), mostly of the germinal center B-cell subtype (GCB-DLBCL) [158]. Some of these lymphomas also contain BCL2 mutations. Single nucleotide variants (SNVs), including some that cause amino acid substitutions and others that are silent, were demonstrated soon after BCL2 was cloned [159, 160]. Detection of similar SNVs in untreated FL ruled out chemotherapy as a cause of these BCL2 mutations [159]. In contrast to the impact of other abnormalities involving BCL2, e.g., the extremely poor prognosis of so-called “double hit” lymphomas that harbor translocations involving both the MYC and BCL2 genes [161], the effects of BCL2 SNVs on DLBCL and FL have been less clear. Recent sequencing of large numbers of primary DLBCL samples and matched germline DNA has demonstrated a high incidence of tumor-associated BCL2 mutations and linked these changes to somatic hypermutation, an activation-induced cytidine deaminase- (AID-) driven mutagenic process that ordinarily generates antibody diversity [162?65]. Because most BCL2 mutations in DLBCL (60?0 ) are synonymous [162] and not associated with any impact on chemosensitivity or survival [165], it has been assumed that BCL2 mutations in DLBCL are passenger mutations. Additional studies have examined BCL2 mutations in FL. More indolent than DLBCL, FL nonetheless carries a 2? /year risk of transformation to a more aggressive neoplasm. Transformed FL (tFL) most often resembles DLBCL morphologically [166, 167] but historically has been quite resistant to therapy [167, 168]. This poor therapeutic response of.

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