Forced Expression of Survivin-2B Abrogates Mitotic Cells and Induces Mitochondria-dependent Apoptosis by Blockade of Tubulin Polymerization and Modulation of Bcl-2, Bax, and Survivin

Ling, Xiang; Cheng, Qing; Black, Jennifer D.; Li, Fengzhi

doi:10.1074/jbc.m705161200

Cited by 40 publications

(33 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although classically studied in tumors, survivin has more recently been found to be a survival factor for proliferating vascular SMCs (35,36). Of the known splice variants of survivin, survivin-2B is noteworthy because, in contrast to other isoforms, it acts as a proapoptotic molecule, and its forced expression in HeLa cells has been found to activate, rather than suppress, caspase-9 and caspase-3 (24). Our findings establish that IGF-1 "resolves" this inherent antagonism among survivin splice variants by terminating the expression of survivin-2B and enhancing survivin expression.…”

Section: Discussionmentioning

confidence: 57%

“…No additional survivin splice variants were observed following WTAP overexpression; however, there was a striking change in the balance of the existing splice forms. In particular, there was with a substantial increase in survivin-2B mRNA, which has been reported to be a proapoptotic isoform (24), and a reciprocal decrease in abundance of survivin, which is antiapoptotic (Fig. 6A, lane 2).…”

Section: Wtap Modulates the Balance Of Survivin Splice Variants Inmentioning

confidence: 99%

See 1 more Smart Citation

Nuclear Degradation of Wilms Tumor 1-associating Protein and Survivin Splice Variant Switching Underlie IGF-1-mediated Survival

Small

Pickering

2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

WTAP (Wilms tumor 1-associating protein) is a recently identified nuclear protein that is essential for mouse embryo development. The Drosophila homolog of WTAP, Fl(2)d, regulates pre-mRNA splicing; however, the role of WTAP in mammalian cells is uncertain. To elucidate a context for WTAP action, we screened growth and survival factors for their effects on WTAP expression in vascular smooth muscle cells (SMCs), a cell type previously found to express WTAP dynamically. This revealed that insulin-like growth factor-1 (IGF-1) uniquely reduced WTAP abundance. This decline in WTAP proved to be necessary for IGF-1 to confer its antiapoptotic properties, which were blocked by transducing the WTAP gene into SMCs. WTAP down-regulation by IGF-1 was mediated by an IGF-1 receptorphosphatidylinositol 3-kinase-Akt signaling axis that directed WTAP degradation via a nuclear 26 S proteasome. Moreover, by promoting the degradation of WTAP, IGF-1 shifted the pre-mRNA splicing program for the survival factor, survivin, to reduce expression of survivin-2B, which is proapoptotic, and increase expression of survivin, which is antiapoptotic. Knockdown of survivin-2B rescued the ability of IGF-1 to promote survival when WTAP was overexpressed. These data uncover a novel regulatory cascade for human SMC survival based on adjusting the nuclear abundance of WTAP to define the splice variant balance among survivin isoforms. Smooth muscle cell (SMC)3 survival is critical to vascular stability (1). This is especially important during atherosclerosis, a condition that depends on replicating SMCs to mechanically stabilize the artery wall. An abundance of proapoptotic stimuli within an atherosclerotic lesion can deplete the SMC population, resulting in plaque rupture and myocardial infarction (1, 2). Pathways that enable SMCs to replicate and perform reparative functions and simultaneously resist apoptotic signals are therefore vital to cardiovascular health.WTAP (Wilms tumor 1-associating protein) is a recently identified nuclear protein that, as its name implies, can interact with the WT1 suppressor protein (3, 4). The precise molecular actions of WTAP are not well understood, but the importance of this protein is highlighted by the early lethality of WTAP-null mouse embryos (5, 6). WTAP is widely expressed in adult tissues and might therefore play a constitutive role. However, expression of WTAP can also be dynamic. We found that WTAP expression in the adult artery wall varied, depending on whether the vessel was quiescent or remodeling. In particular, WTAP abundance decreased as vascular SMCs were induced to proliferate and increased as remodeling subsided and SMC accumulation terminated. Furthermore, overexpression of WTAP in cultured SMCs suppressed their accumulation, whereas WTAP knockdown stimulated population growth. These effects were mediated, at least in part, by the capacity for WTAP to activate apoptosis (4).The basis by which WTAP impacts cell function is uncertain, and several possibilities have been raised. One group has repor...

show abstract

Section: Discussionmentioning

confidence: 57%

Section: Wtap Modulates the Balance Of Survivin Splice Variants Inmentioning

confidence: 99%

Nuclear Degradation of Wilms Tumor 1-associating Protein and Survivin Splice Variant Switching Underlie IGF-1-mediated Survival

Small

Pickering

2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Recently, microtubular depolymerization was found to induce mitochondriadependent apoptotic signaling accompanied with activation of caspase-9 and caspase-3 (35). On the other hand, the treatment with tubulin-binding agent Taxol transactivates the intracellular domain of the Notch receptor and modulates the Notch signaling pathway-dependent survival of several cancer cells (36,37).…”

Section: Discussionmentioning

confidence: 99%

Intracellular β-Tubulin/Chaperonin Containing TCP1-β Complex Serves as a Novel Chemotherapeutic Target against Drug-Resistant Tumors

et al. 2009

View full text Add to dashboard Cite

show abstract

“…To date, four survivin variants have been described: survivin-2α, -2β, -δEx3 and -3B (22). Survivin δEx3 is anti-apoptotic (23), whereas 2α and 2B are potentially pro-apoptotic (24,25). Although it remains unclear whether these splicing variants mediate apoptosis inhibition or induction in TNBC cells, spontaneous apoptosis induced by YM155 is accompanied with the suppression of wild-type survivin and its splicing variants (Fig.…”

Section: Discussionmentioning

confidence: 99%

YM155, a selective survivin suppressant, inhibits tumor spread and prolongs survival in a spontaneous metastatic model of human triple negative breast cancer

Yamanaka

2011

Int J Oncol

View full text Add to dashboard Cite

Abstract. Metastatic triple negative breast cancer [TNBC, with negative expression of estrogen and progesterone receptors and no overexpression of HER2/neu (ErbB-2)] remains a major therapeutic challenge because of its poor overall prognosis and lack of optimal targeted therapies. Survivin has been implicated as an important mediator of breast cancer cell growth and dysfunctions in apoptosis, and its expression correlates with a higher incidence of metastases and patient mortality; thus, survivin is an attractive target for novel anticancer agents. In previous studies, we identified YM155 as a small molecule that selectively suppresses survivin expression. YM155 inhibits the growth of a wide range of human cancer cell lines. Tumor regression induced by YM155 is associated with decreased intratumoral survivin expression, increased apoptosis and a decreased mitotic index. In the present study, we evaluated the antitumor efficacy of YM155 both in vitro and in vivo using preclinical TNBC models. We found that YM155 suppressed survivin expression, including that of its splice variants (survivin 2B, δEx3 and 3B), resulting in decreased cellular proliferation and spontaneous apoptosis of human TNBC cells. In a mouse xenograft model, continuous infusion of YM155 led to the complete regression of subcutaneously established tumors. Furthermore, YM155 reduced spontaneous metastases and significantly prolonged the survival of animals bearing established metastatic tumors in the MDA-MB-231-Luc-D3H2-LN orthotopic model. These results suggest that the survivin-suppressing activity of YM155 may offer a novel therapeutic option for patients with metastatic TNBC. IntroductionBreast cancer is one of the leading causes of cancer death worldwide (1). For patients with local disease, breast cancer is potentially curable by surgical resection combined with adjuvant therapy, including radiation, anti-estrogen therapy and Her2-targeting agents. However, management of metastatic breast cancer is far less successful than treatment of local disease. Despite the recent progress in molecular-targeted therapies, metastatic breast cancer remains the principal cause of breast cancer death and is a major therapeutic challenge for selecting optimal treatment (2).Recent molecular characterization of genetic signatures for patient stratification revealed that triple negative breast cancer (TNBC), with negative expression both of estrogen and progesterone receptors and no overexpression of the Her2 protein, is a high-risk factor with limited therapeutic options. Retrospective studies suggest that TNBC patients represent ~15% of total breast cancers, and that this cancer type may be more aggressive, with rapid tumor growth, a high incidence of metastasis, an increased possibility of distant recurrence, and a higher mortality rate than other breast cancers (3-5). Metastatic TNBC patients have a higher response rate than patients with hormone receptor-positive breast cancer at the initial stage of chemotherapy (6,7). However, the median overall surviva...

show abstract

Forced Expression of Survivin-2B Abrogates Mitotic Cells and Induces Mitochondria-dependent Apoptosis by Blockade of Tubulin Polymerization and Modulation of Bcl-2, Bax, and Survivin

Cited by 40 publications

References 32 publications

Nuclear Degradation of Wilms Tumor 1-associating Protein and Survivin Splice Variant Switching Underlie IGF-1-mediated Survival

Nuclear Degradation of Wilms Tumor 1-associating Protein and Survivin Splice Variant Switching Underlie IGF-1-mediated Survival

Intracellular β-Tubulin/Chaperonin Containing TCP1-β Complex Serves as a Novel Chemotherapeutic Target against Drug-Resistant Tumors

YM155, a selective survivin suppressant, inhibits tumor spread and prolongs survival in a spontaneous metastatic model of human triple negative breast cancer

Contact Info

Product

Resources

About