Identification of a novel splice variant of the human anti-apoptopsis gene survivin

Badran, Adel; Yoshida, Akira; Ishikawa, Kinya; Goi, Takanori; Yamaguchi, Akio; Ueda, Takanori; Inuzuka, Manabu

doi:10.1016/j.bbrc.2003.12.178

Cited by 141 publications

(116 citation statements)

References 22 publications

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“…Transcription from the survivin gene locus gives rise to alternatively spliced transcripts, described in both humans and mice (Mahotka et al, 1999;Badran et al, 2004). Of the human splice variants, survivin-2B is generated by the insertion of an alternative exon; survinin-DEx-3 arises from the removal of exon 3; and survivin-3B results from the introduction of a novel exon 3B (Figure 1) (Mahotka et al, 1999;Badran et al, 2004). Little is known about the differential function or the differential expression of the survinin alternative splice forms or how they might interact with other proteins or themselves.…”

Section: Introductionmentioning

confidence: 99%

Survivin splice variants regulate the balance between proliferation and cell death

et al. 2005

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Survivin is an inhibitor of apoptosis protein that also plays critical roles in regulating the cell cycle and mitosis. Its prominent expression in essentially all human malignancies, and low or absent expression in most normal tissues, suggests that it would be an ideal target for cancerdirected therapy. Impeding development of safe and effective survivin antagonists for clinical use is a lack of understanding of the molecular mechanisms by which survivin differentially affects apoptosis and cell division, in normal and malignant cells. We show that the diverse functional roles of survivin can be explained, in part, by its heterodimerization with survivin splice variants in tumor cells. Survivin and survivin-DEx3 interact within the mitochondria where they may inhibit mitochondrialdependent apoptosis. If the expression of all survivin forms is eliminated by siRNA transfections, cells undergo both apoptosis and defective cell division. Overall, we provide new insights suggesting that targeting specific survivin isoforms, rather than survivin alone, may selectively and effectively destroy tumor cells. These findings are likely to have a significant impact in the design of biologic agents for clinical therapy.

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Section: Introductionmentioning

confidence: 99%

Survivin splice variants regulate the balance between proliferation and cell death

et al. 2005

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“…In addition to the orthodox survivin, several alternatively spliced variants of survivin have been identified: survivin-DEx3 (lacking exon 3) retains the antiapoptotic function; survivin-2B (retaining a part of intron 2 as a cryptic exon) exhibits a marked reduction in antiapoptotic potential; and survivin-3B (retaining a part of intron 3), whose function remains to be determined (Mahotka et al, 1999;Badran et al, 2004). These functionally divergent survivin variants are often simultaneously expressed in cancer cells along with the orthodox survivin (Hirohashi et al, 2002), implying that these variants may be involved in the fine-tuning of survivin action.…”

Section: Introductionmentioning

confidence: 99%

An alternatively spliced survivin variant is positively regulated by p53 and sensitizes leukemia cells to chemotherapy

Zhu

Findley

et al. 2004

Oncogene

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Survivin is a unique member of the inhibitor of apoptosis protein family, and its expression is regulated by p53. Recent identification of several functionally divergent survivin variants augments the complexity of survivin action as well as its regulation. Here we report that survivin-2B (retaining a part of intron 2 as a cryptic exon) is positively regulated by p53, and its overexpression plays a role in sensitizing leukemia cells to chemotherapeutic drug doxorubicin. Doxorubicin treatment activated p53, downregulated survivin and survivin-DEx3 but upregulated survivin-2B in EU-3, an acute lymphocytic leukemia (ALL) cell line with wild-type (wt)-p53 phenotype. In contrast, doxorubicin treatment failed to induce these alterations in EU-6 cells, a mutant-p53 ALL cell line. To specify the role of wt-p53 in regulating survivin and its variants, a temperature-sensitive p53 mutant plasmid p53-143 was transfected into EU-4, a p53-null ALL cell line, to establish a subline EU-4/p53-143. When EU-4/p53-143 cell culture was shifted from 37.5 C to the wt-p53-permissive temperature (32.5 C), the expression of survivin and survivin-DEx3 was decreased whereas survivin-2B expression was increased, confirming the distinct regulatory effect of p53 on survivin and its variants. To clarify the role of survivin-2B in the process of apoptosis, survivin-2B cDNA was cloned into pcDNA3HA vector and transfected into EU-4 cells. Enforced expression of survivin-2B in EU-4 cells inhibited cell growth and sensitized these cells to doxorubicin-induced apoptosis. These results suggest that survivin-2B variant is a proapoptotic factor and its expression is upregulated by p53.

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“…Their expression levels correlate with cancer progression (Li, 2005). Survivin-DEx3 is generated by the removal of exon 3 (Mahotka et al, 1999;Badran et al, 2004;Caldas et al, 2005). The open reading frame of survivin-DEx3 encodes a protein with an interrupted BIR domain and a unique 63 amino-acid long Cterminal tail (Mahotka et al, 1999).…”

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confidence: 99%

Characterisation of the anti-apoptotic function of survivin-ΔEx3 during TNFα−mediated cell death

Wang

Koumi

et al. 2007

Br J Cancer

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Survivin is an oncogenic protein involved in cell division and acts as an anti-apoptotic factor. It is highly expressed in most cancers and is associated with chemotherapy resistance, increased tumour recurrence, and shorter patient survival. This makes anti-survivin therapy an attractive cancer treatment strategy. These functions are mediated by several survivin spliced variants, whose expression may correlate with cancer progression. One of the spliced variants, survivin-DEx3, is known to inhibit apoptosis, through undefined mechanisms. Here, we characterised these mechanisms upon TNFaÀmediated apoptosis, and showed that survivin-DEx3 acts as an adaptor, allowing the formation of a complex between Bcl-2 and activated caspase-3. The Bcl-2/survivin-DEx3 complex, but not survivin-DEx3 itself, inhibits the activity of caspase-3. Bcl-2 is therefore linked to the postmitochondrial apoptotic machinery by survivin-DEx3. Thus, survivin-DEx3 plays a key role in the inhibition of caspase-3 activity, and in the control of the mitochondrial checkpoint of apoptosis. This study suggests that targeting survivin-DEx3, rather than survivin alone, could be relevant for treating human cancers.

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Identification of a novel splice variant of the human anti-apoptopsis gene survivin

Cited by 141 publications

References 22 publications

Survivin splice variants regulate the balance between proliferation and cell death

Survivin splice variants regulate the balance between proliferation and cell death

An alternatively spliced survivin variant is positively regulated by p53 and sensitizes leukemia cells to chemotherapy

Characterisation of the anti-apoptotic function of survivin-ΔEx3 during TNFα−mediated cell death

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