Molecular Mechanisms Associated with the Regulation of Apoptosis by the Two Alternatively Spliced Products of c-Myb

Kumar, Atul; Baker, Stacey J.; Lee, Clement; Reddy, E. Premkumar

doi:10.1128/mcb.23.18.6631-6645.2003

Cited by 21 publications

(23 citation statements)

References 62 publications

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“…E2F-1 has both activities as it is required for T-cell apoptosis in vivo and its overexpression induces apoptosis in a number of cell lines but inhibits apoptosis in others such as Baf-3 cells (Field et al, 1996;Gala et al, 2001). However, increased activity of many transcription factors such as c-Jun, c-Fos, E2F-1, p75 c-Myb, FKH-L1, c-Myc and p53 induces apoptosis or sensitises the cells to proapoptotic stimuli (Harrington et al, 1994;Qin et al, 1994;Lassus et al, 1996;Preston et al, 1996;Bossy-Wetzel et al, 1997;Dijkers et al, 2000;Kumar et al, 2003). Our study shows that this is also the case for Sp1.…”

Section: Discussionsupporting

confidence: 56%

Overexpression of Sp1 transcription factor induces apoptosis

et al. 2006

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Transcription factor Sp1 has recently been shown to be overexpressed in a number of human cancers and its overexpression contributes to malignant transformation. Sp1 regulates the expression of a number of genes participating in multiple aspects of tumorigenesis such as angiogenesis, cell growth and apoptosis resistance. To better understand the role of increased Sp1 levels on apoptosis regulation we have used retroviruses to overexpress this protein in haematopoietic Baf-3 cells and in 3T3 fibroblasts. We have also used inducible expression systems to control ectopic Sp1 levels in different cell types. Surprisingly, Sp1 overexpression on its own induces apoptosis in all the cellular models tested. The apoptotic pathways induced by Sp1 overexpression are cell type specific. Finally, using a truncated form of Sp1, we show that Sp1-induced apoptosis requires its DNA-binding domain. Our results highlight that Sp1 levels in untransformed cells must be tightly regulated as Sp1 overexpression leads to the induction of apoptosis. Our results also suggest that cancer cells overexpressing Sp1 can avoid Sp1-induced apoptosis.

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Section: Discussionsupporting

confidence: 56%

Overexpression of Sp1 transcription factor induces apoptosis

et al. 2006

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“…We therefore examined the splicing patterns of transcripts from selected endogenous genes with roles in transformation and apoptosis, for which alternatively spliced isoforms have been characterized (Supplementary Table 1 online). These genes include known or putative tumor suppressors, such as BIN1, BRCA1, MGEA6, TSC2, VHL and TP73, and proto-oncogenes, such as ERBB2, RPS6KB1 (S6K1), MYBL2 (B-myb) and MYB (C-myb) 7,11,12,26 . The BIN1 protein interacts with the product of the MYC (c-Myc) proto-oncogene, suppressing its oncogenic activity, and is inactivated or deleted in various cancers 11,27 .…”

Section: Effects On Alternative Splicing Of Endogenous Targetsmentioning

confidence: 99%

“…The levels of SF2/ASF also affected the alternative splicing of other oncogenes, including C-myb and B-myb 12 (Supplementary Table 1). In addition, SF2/ASF overexpression promoted the inclusion of exon 5 in the transcription factor gene TEAD1 (TEF-1) and of exon 2 in the splicing factor gene HNRPA2B1 (Fig.…”

Section: Effects On Alternative Splicing Of Endogenous Targetsmentioning

confidence: 99%

The gene encoding the splicing factor SF2/ASF is a proto-oncogene

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Stanchina

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et al. 2007

Nat Struct Mol Biol

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Alternative splicing modulates the expression of many oncogene and tumor-suppressor isoforms. We have tested whether some alternative splicing factors are involved in cancer. We found that the splicing factor SF2/ASF is upregulated in various human tumors, in part due to amplification of its gene, SFRS1. Moreover, slight overexpression of SF2/ASF is sufficient to transform immortal rodent fibroblasts, which form sarcomas in nude mice. We further show that SF2/ASF controls alternative splicing of the tumor suppressor BIN1 and the kinases MNK2 and S6K1. The resulting BIN1 isoforms lack tumor-suppressor activity; an isoform of MNK2 promotes MAP kinase-independent eIF4E phosphorylation; and an unusual oncogenic isoform of S6K1 recapitulates the transforming activity of SF2/ASF. Knockdown of either SF2/ASF or isoform-2 of S6K1 is sufficient to reverse transformation caused by the overexpression of SF2/ASF in vitro and in vivo. Thus, SF2/ASF can act as an oncoprotein and is a potential target for cancer therapy.For about three-quarters of human genes, individual or partial exons can be included in or excluded from different versions of the mature messenger RNA by alternative splicing 1 . Many alternative splicing factors combinatorially affect this process to determine which mRNA isoforms will serve as the templates for protein synthesis in a given cell type, developmental stage or physiological state 2 .SR proteins are a family of RNA-binding proteins that are essential for splicing. They act at multiple steps of spliceosome assembly and function in both constitutive and regulated splicing. Some heterogeneous nuclear ribonucleoprotein (hnRNP) proteins, which rapidly associate with nascent transcripts, have been implicated in the repression of certain alternative splicing events 2 . hnRNP and SR proteins can have antagonistic effects on the alternative splicing of particular exons in several genes 2 . Both types of factor can bind directly to precursor (pre)-mRNA transcripts, eliciting changes in the alternative splicing of various pre-mRNA substrates in a concentration-dependent manner, both in vitro and in transfection experiments 3,4 . Thus, changes in the expression of these proteins can affect the Reprints and permissions information is available online at

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“…This form is translated from a c-myb mRNA variant, which contains an insertion of 363 bases between exons 9 and 10 leading to disruption of the leucine zipper. This variant is a more potent transactivator than c-Myb, and 32Dcl3 cells expressing p89 c-Myb are considerably more resistant than parental or wildtype c-Myb-expressing cells to apoptosis induced by growth factor deprivation (52). A 2-amino acid leucine zipper mutant of wild-type c-Myb was not as effective as p89 c-Myb (51), suggesting that other modifications/interactions of the region that includes the leucine zipper domain may be necessary to enhance the effects of c-Myb.…”

Section: Effects Of Stable C-myb Mutants On Normal and Bcr/ablexpressmentioning

confidence: 99%