MCL-1S, a Splicing Variant of the Antiapoptotic BCL-2 Family Member MCL-1, Encodes a Proapoptotic Protein Possessing Only the BH3 Domain

Bae, Jang–Ho; Leo, Chandra P.; Hsu, Sze-Bi; Hsueh, Aaron J. W.

doi:10.1074/jbc.m909826199

Cited by 251 publications

(242 citation statements)

References 52 publications

Supporting

Mentioning

228

Contrasting

Unclassified

Order By: Relevance

“…Previous studies have indicated that Mcl-1S might have pro-rather than anti-apoptotic properties. 53 We saw no evidence for the generation of mature Mcl-1S protein before or after SSA treatment in CLL or Ramos cells even in the presence of Z-VAD, suggesting that the Mcl-1s form is not stable and/or biologically functional in these cells. Supporting our hypothesis that Mcl-1L reduction is the primary reason for the apoptosis induced by SSA, we saw tight correlation between the reduction in MCL-1L transcripts, protein expression and apoptosis.…”

Section: Discussionmentioning

confidence: 57%

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

et al. 2015

View full text Add to dashboard Cite

The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA), is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose-and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression.However, normal B and T cells were less sensitive than CLL cells (p=0.006 and p<0.001, respectively).

show abstract

Section: Discussionmentioning

confidence: 57%

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

et al. 2015

View full text Add to dashboard Cite

show abstract

“…44,45 Transcripts of this gene show alternative splicing, and 2 variants encoding distinct isoforms have been identified. 46 The product of the longer transcript enhances cell survival by inhibiting apoptosis, while the alternatively spliced shorter gene product promotes apoptosis. We cannot distinguish these transcripts because the 3 different probe sets contained on the Affymetrix chip detect both transcript variants.…”

Section: Discussionmentioning

confidence: 99%

Genomic gains on chromosome 1q in retinoblastoma: Consequences on gene expression and association with clinical manifestation

Gratias

Schüler

Hitpass

et al. 2005

Intl Journal of Cancer

View full text Add to dashboard Cite

Many retinoblastomas (Rbs) show genomic alterations in addition to mutational loss of both normal RB1 alleles. The most frequent of these changes are gains on chromosomes 1q and 6p and losses on 16q. To identify the genes targeted by gains on chromosome 1q, we used quantitative-multiplex PCR to determine DNA copy number changes in 76 primary tumors and 6 Rb cell lines. In addition, in 21 of these tumors, gene expression was analyzed by cDNA microarray hybridization. Increased copy numbers of loci on chromosome 1q were present in 34 (45%) primary tumors and in all 6 cell lines. Two regions of gain emerged, one in 1q32 and another in 1q21. Tumors with 1q gains showed higher RNA expression of several genes in these 2 regions. The clinical manifestation of tumors with and without gains was similar with regard to many aspects, including size, necrosis and calcification. However, the distribution of age at diagnosis was remarkably distinct, with earlier diagnosis in tumors without gains. This suggests that these tumors either are initiated earlier or grow faster than tumors with gains. This association with clinical manifestation indicates that gains on 1q are significant for the biology of Rb. The genes on 1q with copy number gains and overexpression are candidates that need to be tested for their individual contribution to the progression of Rb. ' 2005 Wiley-Liss, Inc.

show abstract

“…7B). 42,43 In addition, belinostat up-regulated expression of the BH3-only apoptotic activator, BIM about 2-3-fold. Vincristine treatment had little effect on expression of either MCL-1 or BIM.…”

Section: Belinostat Curtails Vincristine-induced Sac Activation and Cmentioning

confidence: 99%

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Havas

Rodrigues

Bhakta

et al. 2016

Cancer Biology & Therapy

View full text Add to dashboard Cite

Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in combination with a variety of other drugs. However, rational selection of companion therapeutics for HDACi is difficult due to their poorly-understood, celltype specific mechanisms of action. To address this, we developed a pre-clinical model system of sensitivity and resistance to the HDACi belinostat using DLBCL cell lines. In the current study, we demonstrate that cell lines sensitive to the cytotoxic effects of HDACi undergo early mitotic arrest prior to apoptosis. In contrast, HDACi-resistant cell lines complete mitosis after a short delay and arrest in G1. To force mitotic arrest in HDACi-resistant cell lines, we used low dose vincristine or paclitaxel in combination with belinostat and observed synergistic cytotoxicity. Belinostat curtails vincristine-induced mitotic arrest and triggers a strong apoptotic response associated with downregulated MCL-1 expression and upregulated BIM expression. Resistance to microtubule targeting agents (MTAs) has been associated with their propensity to induce polyploidy and thereby increase the probability of genomic instability that enables cancer progression. Co-treatment with belinostat effectively eliminated a vincristine-induced, actively cycling polyploid cell population. Our study demonstrates that vincristine sensitizes DLBCL cells to the cytotoxic effects of belinostat and that belinostat prevents polyploidy that could cause vincristine resistance. Our findings provide a rationale for using low dose MTAs in conjunction with HDACi as a potential therapeutic strategy for treatment of aggressive DLBCL.

show abstract

MCL-1S, a Splicing Variant of the Antiapoptotic BCL-2 Family Member MCL-1, Encodes a Proapoptotic Protein Possessing Only the BH3 Domain

Abstract: MCL-1 (myeloid cell leukemia-1) is an antiapoptotic

Cited by 251 publications

References 52 publications

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

Genomic gains on chromosome 1q in retinoblastoma: Consequences on gene expression and association with clinical manifestation

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Contact Info

Product

Resources

About