Splice variants in apoptotic pathway
Elimination of superfluous or mutated somatic cells is provided by various mechanisms including apoptosis, and deregulation of apoptotic signaling pathways contributes to oncogenesis. 40 years have passed since the term “apoptosis” was introduced by Kerr et al. in 1972; among the programmed cell dea...
Збережено в:
| Дата: | 2012 |
|---|---|
| Автори: | , , |
| Формат: | Стаття |
| Мова: | English |
| Опубліковано: |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2012
|
| Назва видання: | Experimental Oncology |
| Теми: | |
| Онлайн доступ: | https://nasplib.isofts.kiev.ua/handle/123456789/139085 |
| Теги: |
Додати тег
Немає тегів, Будьте першим, хто поставить тег для цього запису!
|
| Назва журналу: | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| Цитувати: | Splice variants in apoptotic pathway / K. Miura, W. Fujibuchi, M. Unno // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 212-217. — Бібліогр.: 71 назв. — англ. |
Репозитарії
Digital Library of Periodicals of National Academy of Sciences of Ukraine| id |
nasplib_isofts_kiev_ua-123456789-139085 |
|---|---|
| record_format |
dspace |
| spelling |
nasplib_isofts_kiev_ua-123456789-1390852025-02-09T20:16:04Z Splice variants in apoptotic pathway Miura, K. Fujibuchi, W. Unno, M. Reviews Elimination of superfluous or mutated somatic cells is provided by various mechanisms including apoptosis, and deregulation of apoptotic signaling pathways contributes to oncogenesis. 40 years have passed since the term “apoptosis” was introduced by Kerr et al. in 1972; among the programmed cell death, a variety of therapeutic strategies especially targeting apoptotic pathways have been investigated. Alternative precursor messenger RNA splicing, by which the process the exons of pre-mRNA are spliced in different arrangements to produce structurally and functionally distinct mRNA and proteins, is another field in progress, and it has been recognized as one of the most important mechanisms that maintains genomic and functional diversity. A variety of apoptotic genes are regulated through alternative pre-mRNA splicing as well, some of which have important functions as pro-apoptotic and anti-apoptotic factors. In this article we summarized splice variants of some of the apoptotic genes including BCL2L1, BIRC5, CFLAR, and MADD, as well as the regulatory mechanisms of alternative splicing of these genes. If the information of the apoptosis and aberrant splicing in each of malignancies is integrated, it will become possible to target proper variants for apoptosis, and the trans-elements themselves can become specific targets of cancer therapy as well. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”. The authors would appreciate this opportunity to submit our work to the Special Issue of Experimental Oncology (National Academy of Sciences of Ukraine). 2012 Article Splice variants in apoptotic pathway / K. Miura, W. Fujibuchi, M. Unno // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 212-217. — Бібліогр.: 71 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/139085 en Experimental Oncology application/pdf Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| language |
English |
| topic |
Reviews Reviews |
| spellingShingle |
Reviews Reviews Miura, K. Fujibuchi, W. Unno, M. Splice variants in apoptotic pathway Experimental Oncology |
| description |
Elimination of superfluous or mutated somatic cells is provided by various mechanisms including apoptosis, and deregulation of apoptotic signaling pathways contributes to oncogenesis. 40 years have passed since the term “apoptosis” was introduced by Kerr et al. in 1972; among the programmed cell death, a variety of therapeutic strategies especially targeting apoptotic pathways have been investigated. Alternative precursor messenger RNA splicing, by which the process the exons of pre-mRNA are spliced in different arrangements to produce structurally and functionally distinct mRNA and proteins, is another field in progress, and it has been recognized as one of the most important mechanisms that maintains genomic and functional diversity. A variety of apoptotic genes are regulated through alternative pre-mRNA splicing as well, some of which have important functions as pro-apoptotic and anti-apoptotic factors. In this article we summarized splice variants of some of the apoptotic genes including BCL2L1, BIRC5, CFLAR, and MADD, as well as the regulatory mechanisms of alternative splicing of these genes. If the information of the apoptosis and aberrant splicing in each of malignancies is integrated, it will become possible to target proper variants for apoptosis, and the trans-elements themselves can become specific targets of cancer therapy as well. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”. |
| format |
Article |
| author |
Miura, K. Fujibuchi, W. Unno, M. |
| author_facet |
Miura, K. Fujibuchi, W. Unno, M. |
| author_sort |
Miura, K. |
| title |
Splice variants in apoptotic pathway |
| title_short |
Splice variants in apoptotic pathway |
| title_full |
Splice variants in apoptotic pathway |
| title_fullStr |
Splice variants in apoptotic pathway |
| title_full_unstemmed |
Splice variants in apoptotic pathway |
| title_sort |
splice variants in apoptotic pathway |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2012 |
| topic_facet |
Reviews |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/139085 |
| citation_txt |
Splice variants in apoptotic pathway / K. Miura, W. Fujibuchi, M. Unno // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 212-217. — Бібліогр.: 71 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
AT miurak splicevariantsinapoptoticpathway AT fujibuchiw splicevariantsinapoptoticpathway AT unnom splicevariantsinapoptoticpathway |
| first_indexed |
2025-11-30T10:11:13Z |
| last_indexed |
2025-11-30T10:11:13Z |
| _version_ |
1850209704377057280 |
| fulltext |
212 Experimental Oncology 34, 212–217, 2012 (September)
SPLICE VARIANTS IN APOPTOTIC PATHWAY
K. Miura1,*, W. Fujibuchi2, M. Unno1
1Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, 980–8574 Japan
2Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606–8507 Japan
Elimination of superfluous or mutated somatic cells is provided by various mechanisms including apoptosis, and deregulation of apop-
totic signaling pathways contributes to oncogenesis. 40 years have passed since the term “apoptosis” was introduced by Kerr et al.
in 1972; among the programmed cell death, a variety of therapeutic strategies especially targeting apoptotic pathways have been in-
vestigated. Alternative precursor messenger RNA splicing, by which the process the exons of pre-mRNA are spliced in different ar-
rangements to produce structurally and functionally distinct mRNA and proteins, is another field in progress, and it has been recognized
as one of the most important mechanisms that maintains genomic and functional diversity. A variety of apoptotic genes are regulated
through alternative pre-mRNA splicing as well, some of which have important functions as pro-apoptotic and anti-apoptotic factors.
In this article we summarized splice variants of some of the apoptotic genes including BCL2L1, BIRC5, CFLAR, and MADD, as well
as the regulatory mechanisms of alternative splicing of these genes. If the information of the apoptosis and aberrant splicing in each
of malignancies is integrated, it will become possible to target proper variants for apoptosis, and the trans-elements themselves can
become specific targets of cancer therapy as well. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”.
Key Words: apoptosis, alternative pre-mRNA splicing, splice variants, malignancy, therapeutics.
INTRODUCTION
Elimination of superfluous or mutated somatic cells
is provided by various mechanisms including apoptosis
[1], and deregulation of apoptotic signaling pathways
contributes to oncogenesis. It was 40 years ago when
Kerr, Wyllie, and Currie coined the term “apoptosis”
to describe a special form of programmed cell death
and published their original article on apoptosis [2].
Since that time the concept of apoptosis has con-
tributed much to the various fields of biology and
medicine especially in cancer research, and a variety
of therapeutic strategies especially targeting apoptotic
pathways have been investigated. On the other hand,
alternative precursor messenger RNA (pre-mRNA)
splicing, by which the process the exons of pre-mRNA
are spliced in different arrangements to produce struc-
turally and functionally distinct mRNA and proteins,
is another field in progress [3]. After the completion
of the Human Genome Project in 2004, alternative
pre-mRNA splicing has been recognized as one of the
most important mechanisms that maintains genomic
and functional diversity. A variety of apoptotic genes
are regulated through alternative pre-mRNA spli-
cing as well, some of which have important functions
as pro-apoptotic and anti-apoptotic factors. In this
article, we summarized splice variants of some of the
apoptotic genes as well as the regulatory mechanisms
of alternative splicing of those genes.
APOPTOTIC PATHWAY
There are two main pathways in apoptosis: the
death receptor-mediated apoptotic pathway (extrinsic
pathway) and the mitochondrial-mediated apoptotic
pathway (intrinsic pathway) (Fig. 1).
Fig. 1. A scheme of apoptotic pathway
The death receptor-mediated apoptotic path-
way is initiated when tumor necrosis factor (TNF),
TNF-related apoptosis-inducing ligand (TRAIL, also
known as apolipoprotein-2L (APO-2L)) or FAS ligand
(APO-1) bind to their receptors (TNFR, TRAIL-R and
FAS, respectively), in association with adaptor mol-
ecules such as FAS-associated death domain (FADD)
or TNFR-associated death domain (TRADD), and ini-
Received: June 11, 2012
*Correspondence: FAX: +81-22-717-7209 ;
E-mail: k-miura@surg1.med.tohoku.ac.jp
Abbreviations used: (Y)n — poly-pyrimidine tract; 3´SS — 3´ splice
site; 5´SS — 5´ splice site; APAF1 — apoptosis-activating factor-1;
APO-2L — apolipoprotein-2L; BCL2L1 — BCL2-like 1; BIR —
baculovirus IAP repeat; BIRC5 — baculoviral IAP repeat containing
5; CFLAR — CASP8- and FADD-like apoptosis regulator; DD —
death domain; DED — death effecter domain; DIABLO — direct
IAP-binding protein with low PI; DISC — death-inducing signaling
complex; ESE — exonic splice enhancer; ESS — exonic splice
silencer; FADD — FAS-associated death domain; hnRNP — hetero-
geneous nuclear ribonucleoprotein; IAP — inhibitor of apoptosis
protein; ISE — intronic splice enhancer; ISS — intronic splice
silencer; MADD — MAP-kinase activating death domain; MAP —
mitogen-activated protein; pre-mRNA — precursor messenger
RNA; Smac — second mitochondria-derived activator of caspases;
SR protein — serine/arginine-rich protein; TNF — tumor necrosis
factor; TRADD — TNFR-associated death domain; TRAIL — TNF-re-
lated apoptosis-inducing ligand.
Exp Oncol 2012
34, 3, 212–217
INVITED REVIEW
Experimental Oncology 34, 212–217, 2012 (September) 213
tiator caspases-8 and -10 are cleaved and activated,
thus resulting in the activation of executor caspases-3,
-6 and -7 and culminating in apoptosis. On the other
hand, the mitochondrial-mediated apoptotic pathway
is initiated when pro-apoptotic proteins release free
cytosolic cytochrome c. Once released, cytochrome
c promotes the assembly of a caspase-activating
complex termed the apoptosome, which includes
apoptosis-activating factor-1 (APAF1), dATP, and
pro-caspase-9. The apoptosome activity functionally
corresponds to the activity of caspase-9, and it acti-
vates executor caspases-3, -6, and -7, thus inducing
apoptosis. The inhibitor of apoptosis protein (IAP)
proteins such as cIAP1, cIAP2, and XIAP can prevent
the proteolytic processing of pro-caspases-3, -6, and
-7 by blocking the cyto chrome c-induced activation
of pro-caspase-9 in the intrinsic pathway; in contrast,
these IAP proteins do not act in the extrinsic pathway
[4]. APAF1/cytochrome c-independent and second
mitochondria-derived activator of caspases (Smac)/
direct IAP-binding protein with low PI (DIABLO)-depen-
dent induction of apoptosis have also been reported.
Alternative models of programmed cell death have
been proposed, but still remain to be further clarified,
including autophagy, paraptosis, mitotic catastro-
phe, and the descriptive model of apoptosis-like and
necrosis-like programmed cell death [1, 5].
ALTERNATIVE PRE-mRNA SPLICING
Pre-mRNA splicing is a mechanism that removes
introns from pre-mRNA and binds exons, eventu-
ally generating mature mRNA (Fig. 2). The process
of pre-mRNA splicing is regulated by two elements:
cis-elements and trans-elements, and the cis-ele-
ments are bound by the trans-elements in pre-mRNA
splicing. Among the cis-elements, consensus splice
sites are essential for pre-mRNA splicing and are
comprised of a 5´splice site (5´SS), a branch point
motif, a poly-pyrimidine tract ((Y)n), and a 3´splice
site (3´SS) (Fig. 3). Among the consensus splice sites,
the 5´SS is also known as a splice donor site and the
3´SS is also known as a splice acceptor site. Splice
enhancers and silencers are known as cis-regulatory
elements, and both of these sites are important for
the recognition of the 5´SS and 3´SS regions, and
depending on their localization within the genome,
splice enhancers and silencers are subclassified
into exonic splice enhancers (ESEs), intronic splice
enhancers (ISEs), exonic splice silencers (ESSs)
or intronic splice silencers (ISSs). Among the known
trans-elements, spliceosomes are multicomponent
complexes essential for pre-mRNA splicing. ESEs
are predominantly bound and recognized by mem-
bers of serine/arginine-rich proteins (SR proteins,
symbolized by SRp) and SR-like proteins. However,
heterogeneous nuclear ribonucleoproteins (hnRNPs)
commonly bind to ESSs and ISSs. In many cases,
hnRNPs block spliceosome assembly, thus resulting
in exon skipping. Several of tissue-specific SR proteins
and hnRNPs have recently been identified. Aberrant
alternative pre-mRNA splicing in malignancies can
be subclassified into two categories: (I) the generation
of an aberrant splice variant as an individual transcript
and (II) an aberrant expression profile of splice variants
as an entire set of transcripts in malignant cells (Fig. 3).
Fig. 2. Alternative pre-mRNA splicing. Seven types of alternative
splicing were indicated
Fig. 3. Regulatory mechanism of alternative pre-mRNA splicing
and its alteration in malignancies. Cis-elements are indicated
with rectangles and trans-elements are indicated with ellipses.
In the nucleotide sequences, Y denotes a pyrimidine (U or C) and
R denotes a purine (G or A). ESE, exonic splice enhancer; ESS,
exonic splice silencer; hnRNP, heterogeneous nuclear ribonu-
cleoprotein; ISE, intronic splice enhancer; ISS, intronic splice
silencer; snRNP, small nuclear ribonucleoprotein; SR, serine/
arginine-rich protein; SS, splice site; U2AF, U2 small nuclear
ribonucleoprotein auxiliary factor
SPLICE VARIANTS IN APOPTOTIC
PATHWAY
Expression profiles of genes in the apoptotic path-
way can also be regulated by alternative pre-mRNA
splicing in both normal and malignant tissues, and
some of those, BCL2L1, BIRC5, CFLAR, and MADD,
will be highlighted in this session (Fig. 4).
BCL2-like 1 (BCL2L1)
Apoptotic factors of the BCL2 family are classified
into two subgroups: anti-apoptotic (e.g., BCL2, MCL1,
and Bcl-xL) and pro-apoptotic (e.g., BAX and Bcl-xS)
[6], and the two subgroups differ in the number and
variety of BH domains they contain [7]. In 1993 Boise
et al. isolated BCL2-like 1 (BCL2L1) gene which func-
tions as a BCL2-independent regulator of apoptosis
(Fig. 1) [8], and alternative splicing resulted in two
distinct BCL2L1 mRNA isoforms: the larger variant
(Bcl-xL) which is similar in size and predicted structure
to BCL2 and the smaller variant (Bcl-xS) which inhibits
the ability of BCL2 to enhance the survival (Fig. 4 a).
214 Experimental Oncology 34, 212–217, 2012 (September)
Fig. 4. Splice variants of genes in the apoptotic pathway. (a)
BCL2L1, (b) BIRC5, (c) CFLAR, and (d) MADD. For each of the
genes, pre-mRNA is indicated at the top, and mature mRNAs
are indicated in the bottom. ID numbers of mRNAs and the
numbers of amino acids were referred to the NCBI database
(as of June 1, 2012)
The overexpression of Bcl-xL confers resistance
to apoptosis (see Fig. 1); in contrast, Bcl-xS can
induce apoptosis and alleviate multidrug resistance;
hence the regulation of alternative splicing of the
BCL2L1 gene has been intensely explored since the
2000s [6, 9–21]. hnRNP F/H was reported to modu-
late the alternative splicing of BCL2L1 gene [9], and
SC35, a member of the SR proteins family, is required
to switch the alternative splicing profile of various
apoptotic genes such as CFLAR, CASP8, CASP9,
and BCL2L1, towards the expression of pro-apop-
totic splice variants [12]. Treatments with a chemical
compound emetine dihydrochloride (CAS number:
316-42-7) down-regulated the level of Bcl-xL mRNA
[11]. In 2012 Michelle et al. at Universite de Sherbrooke
(Quebec, Canada) [6] identified four cis-elements
in exon 2 of the BCL2L1 gene which contribute to the
splicing control: B2, B3, B1, and SB1 regions.
Baculoviral IAP repeat containing 5 (BIRC5,
survivin)
In the process of apoptosis, the IAP family prevents
apoptosis through direct caspase and pro-caspase
inhibition (Fig. 1). The IAP family members are de-
fined by the presence of a baculovirus IAP repeat
(BIR) domain [22, 23]; currently seven genes have
been isolated in this family: XIAP, cIAP1, cIAP2, ILP2,
BRUCE, BIRC5 (survivin) and livin. The IAP proteins
are abnormally regulated and expressed in the ma-
jority of human malignancies at elevated levels, and
an increasing amount of evidence has been recently
accumulated regarding the effects of survivin on the
anti-apoptotic pathway; hence survivin has been in-
vestigated as a therapeutic target for malignancies.
Several of splice variants of survivin have been
reported (Fig. 4 b). In 2007 Sampath and Pelus
published a detailed review on alternative splice vari-
ants of survivin [24]. It seems that the splice variant
Sur2B was regarded as pro-apoptotic until the middle
of 2000s; the results of recent studies, however,
indicate different outcome [25–27]. In 2011 Huang
et al. reported that the wild-type survivin (SurWT),
Sur-DeltaEx3, Sur2B, and Sur-2alpha splice variants
were significantly elevated in astrocytoma and were
associated with tumor grade and poorer prognosis
[26], and Vivas-Mejia’s study on taxane-resistant
ovarian cancer cells showed that Sur-2B was more
abundant in taxane-resistant cells than in taxane-
sensitive cells [27]. These results should be compre-
hensively organized to develop therapeutic agents
to target the variants. Currently novel drugs targeting
sirvivin such as LY2181308 [28] and YM155 [29] are
under development, and recently amiloride was also
reported to regulate alternative splicing of survivin
as well as APAF1 and CRK [16].
CASP8- and FADD-like apoptosis regulator
(CFLAR)
By searching EST databases for sequences
of FADD, which forms a death-inducing signaling com-
plex (DISC) with FAS-L, FAS, and pro-caspase-8 for
the apoptotic pathway (Fig. 1), in 1997 Shu et al.
reported cDNAs encoding a protein which they des-
ignated CASPER [30], and several groups simultane-
ously isolated genes such as CASH, MRIT, CLARP and
others, all of which turned out to be a single gene. This
gene is currently registered as CASP8- and FADD-
like apoptosis regulator (CFLAR) with several types
of splice variants in the NCBI database (Fig. 4 c).
CFLAR has two death effecter domains (DEDs) only,
in contrast to FADD, which have two death domains
(DDs), and caspase-8 and -10, both of which have two
DEDs along with caspase domain.
CFLAR is a major resistance factor and critical anti-
apoptotic regulator that inhibits TNF-alpha, FAS-L, and
TRAIL-induced apoptosis (Fig. 1) as well as chemo-
therapy-triggered apoptosis in malignant cells. CFLAR
binds to FADD and/or caspase-8 or -10 in a ligand-
dependent or ligand-independent fashion, which
in turn prevents DISC formation and subsequent
activation of the caspase cascade [31]. 13 distinct
splice variants of CFLAR have been identified at the
mRNA level [32–37], and CFLAR is expressed as long
(c-FLIPL), short (c-FLIPS), and c-FLIPR splice variants
in human cells (Fig. 4 c). Although CFLAR is a major
resistance factor and critical anti-apoptotic regulator,
the functional differences of the isoforms are still under
exploration, and a cell-type specific pro-apoptotic role,
Experimental Oncology 34, 212–217, 2012 (September) 215
depending on caspase-8 to c-FLIPL ratio, has also
been reported [38].
Mitogen-activated protein (MAP)-kinase acti-
vating death domain (MADD)
In 1996 Chow and Lee reported the cDNA sequence
of mitogen-activated protein (MAP)-kinase activat-
ing death domain (MADD), a novel human gene that
is differentially expressed in normal and neoplastic
cells [39]. MADD is implicated in cancer cell survival,
proliferation, apoptosis, and other regulated functions
[40]. Recently Prabhaker’s laboratory at University
of Illinois at Chicago has published a series of their
studies on splice variants of MADD gene and their
association with apoptosis [41–45]. The MADD gene
encodes at least six different splice variants (Fig. 4 d),
of which four variants, namely IG20pa, MADD, IG20-
SV2, and DENN-SV, are expressed more ubiquitously
[40]. Of these, MADD and DENN-SV are constitutively
expressed, whereas the IG20pa and IG20-SV2 may
or may not be expressed [40].
Other apoptotic genes with splice variants
In addition, splice variants which may have differen-
tial functions on apoptosis have been reported in some
of other genes such as RBM5 [46–48], ING family
[49–51], androgen receptor (AR) [52–54], BRCA1 as-
sociated RING domain 1 (BARD1) [55, 56], caspase
8 (CASP8) [57, 58], Kruppel-like factor 6 (KLF6) [59,
60], myeloid cell leukemia sequence 1 (MCL1) [13,
61], and spleen tyrosine kinase (SYK) genes [62, 63].
THERAPEUTIC STRATEGIES TO TARGET
SPLICE VARIANTS
In the present article we summarized splice variants
of genes in the apoptotic pathway. Novel technolo-
gies such as microarray have enabled us to compre-
hensively screen alternative splicing, and the recent
advance of sequencing technology will give us more
powerful method to understand the whole picture
of this field [64, 65]. The research on the mechanism
of alternative pre-mRNA splicing [66, 67] and the
trans-elements [68] are in progress, and the in silico
computer predictions play another important role [69,
70] although they do not always correlate with in vitro
and in vivo results. On the other hand, the experimental
approaches of apoptosis and oncology are essential
for the progress of research in this field.
The information of apoptosis will help us develop
new strategies of cancer therapeutics. To target splice
variants of apoptosis-associated genes, chemical
compounds as small molecules are as important
as ever, and RNA interference, antisense oligonucle-
otides, and splice-switching oligonucleotides [71]
as well as monoclonal antibodies are new strategies
to target specific sequences. If the information of the
apoptosis and aberrant splicing in each of malignan-
cies is integrated, it will become possible to target
proper variants for apoptosis, and the trans-elements
themselves can become specific targets of cancer
therapy as well.
ACKNOWLEDGEMENT
The authors would appreciate this opportunity
to submit our work to the Special Issue of Experimental
Oncology (National Academy of Sciences of Ukraine).
REFERENCES
1. Philchenkov A, Zavelevich M, Kroczak TJ, Los M.
Caspases and cancer: mechanisms of inactivation and new
treatment modalities. Exp Oncol 2004; 26: 82–97.
2. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic bio-
logical phenomenon with wide-ranging implications in tissue
kinetics. Br J Cancer 1972; 26: 239–57.
3. Miura K, Fujibuchi W, Sasaki I. Alternative pre-mRNA
splicing in digestive tract malignancy. Cancer Sci 2011;
102: 309–16.
4. Miura K, Karasawa H, Sasaki I. cIAP2 as a therapeutic
target in colorectal cancer and other malignancies. Expert Opin
Ther Targets 2009; 13: 1333–45.
5. Long JS, Ryan KM. New frontiers in promoting tumour
cell death: targeting apoptosis, necroptosis and autophagy.
Oncogene 2012 [Epub ahead of print].
6. Michelle L, Cloutier A, Toutant J, et al. Proteins as-
sociated with the exon junction complex also control the
alternative splicing of apoptotic regulators. Mol Cell Biol
2012; 32: 954–67.
7. Youle RJ, Strasser A. The BCL-2 protein family: op-
posing activities that mediate cell death. Nat Rev Mol Cell
Biol 2008; 9: 47–59.
8. Boise LH, González-García M, Postema CE, et al. bcl-
x, a bcl-2-related gene that functions as a dominant regulator
of apoptotic cell death. Cell 1993; 74: 597–608.
9. Garneau D, Revil T, Fisette JF, Chabot B. Heteroge-
neous nuclear ribonucleoprotein F/H proteins modulate the
alternative splicing of the apoptotic mediator Bcl-x. J Biol
Chem 2005; 280: 22641–50.
10. Paronetto MP, Achsel T, Massiello A, et al. The RNA-
binding protein Sam68 modulates the alternative splicing
of Bcl-x. J Cell Biol 2007; 176: 929–39.
11. Boon-Unge K, Yu Q, Zou T, et al. Emetine regulates
the alternative splicing of Bcl-x through a protein phosphatase
1-dependent mechanism. Chem Biol 2007; 14: 1386–92.
12. Merdzhanova G, Edmond V, De Seranno S, et al.
E2F1 controls alternative splicing pattern of genes involved
in apoptosis through upregulation of the splicing factor SC35.
Cell Death Differ 2008; 15: 1815–23.
13. Kim MH. Protein phosphatase 1 activation and alterna-
tive splicing of Bcl-X and Mcl-1 by EGCG + ibuprofen. J Cell
Biochem 2008; 104: 1491–9.
14. Montes M, Cloutier A, Sánchez-Hernández N, et al.
TCERG1 regulates alternative splicing of the Bcl-x gene
by modulating the rate of RNA polymerase II transcription.
Mol Cell Biol 2012; 32: 751–62.
15. Chang JG, Yang DM, Chang WH, et al. Small mol-
ecule amiloride modulates oncogenic RNA alternative splicing
to devitalize human cancer cells. PLoS One 2011; 6: e18643.
16. Chang WH, Liu TC, Yang WK, et al. Amiloride
modulates alternative splicing in leukemic cells and resensi-
tizes Bcr-AblT315I mutant cells to imatinib. Cancer Res 2011;
71: 383–92.
17. Shkreta L, Michelle L, Toutant J, et al. The DNA da-
mage response pathway regulates the alternative splicing of the
apoptotic mediator Bcl-x. J Biol Chem 2011; 286: 331–40.
18. Bauman JA, Li SD, Yang A, et al. Anti-tumor activity
of splice-switching oligonucleotides. Nucleic Acids Res 2010;
38: 8348–56.
216 Experimental Oncology 34, 212–217, 2012 (September)
19. Moore MJ, Wang Q, Kennedy CJ, Silver PA. An al-
ternative splicing network links cell-cycle control to apoptosis.
Cell 2010; 142: 625–36.
20. Revil T, Pelletier J, Toutant J, et al. Heterogeneous
nuclear ribonucleoprotein K represses the production
of pro-apoptotic Bcl-xS splice isoform. J Biol Chem 2009;
284: 21458–67.
21. Zhou A, Ou AC, Cho A, et al. Novel splicing factor
RBM25 modulates Bcl-x pre-mRNA 5’ splice site selection.
Mol Cell Biol 2008; 28: 5924–36.
22. Hinds MG, Norton RS, Vaux DL, Day CL. Solution
structure of a baculoviral inhibitor of apoptosis (IAP) repeat.
Nat Struct Biol 1999; 6: 648–51.
23. Sun C, Cai M, Gunasekera AH, et al. NMR struc-
ture and mutagenesis of the inhibitor-of-apoptosis protein
XIAP. Nature 1999; 401: 818–22.
24. Sampath J, Pelus LM. Alternative splice variants
of survivin as potential targets in cancer. Curr Drug Discov
Technol 2007; 4: 174–91.
25. Nakano J, Huang C, Liu D, et al. The clinical signifi-
cance of splice variants and subcellular localisation of survivin
in non-small cell lung cancers. Br J Cancer 2008; 98: 1109–17.
26. Huang Y, Chen X, Chen N, et al. Expression and
prognostic significance of survivin splice variants in diffusely
infiltrating astrocytoma. J Clin Pathol 2011; 64: 953–9.
27. Vivas-Mejia PE, Rodriguez-Aguayo C, Han HD,
et al. Silencing survivin splice variant 2B leads to antitumor
acti vity in taxane-resistant ovarian cancer. Clin Cancer Res
2011; 17: 3716–26.
28. Church DN, Talbot DC. Survivin in solid tumors: ra-
tionale for development of inhibitors. Curr Oncol Rep 2012;
14: 120–8.
29. Nakamura N, Yamauchi T, Hiramoto M, et al. ILF3/
NF110 is a target of YM155, a suppressant of survivin. Mol
Cell Proteomics 2012; 11: M111.013243.
30. Shu HB, Halpin DR, Goeddel DV. Casper is a FADD-
and caspase-related inducer of apoptosis. Immunity 1997;
6: 751–63.
31. Safa AR, Pollok KE. Targeting the antiapoptotic
protein c-FLIP for cancer therapy. Cancers (Basel) 2011;
3: 1639–71.
32. Micheau O. Cellular FLICE-inhibitory protein: an at-
tractive therapeutic target? Expert Opin Ther Targets 2003;
7: 559–73.
33. Blomberg J, Höglund A, Eriksson D, et al. Inhibition
of cellular FLICE-like inhibitory protein abolishes insensitivity
to interferon-α and death receptor stimulation in resistant vari-
ants of the human U937 cell line. Apoptosis 2011; 16: 783–94.
34. Ewald F, Ueffing N, Brockmann L, et al. The role
of c-FLIP splice variants in urothelial tumours. Cell Death
Dis 2011; 2: e245.
35. Shirley S, Micheau O. Targeting c-FLIP in cancer.
Cancer Lett 2010 [Epub ahead of print].
36. Bijangi-Vishehsaraei K, Saadatzadeh MR, Huang S,
et al. 4-(4-Chloro-2-methylphenoxy)- N-hydroxybutanamide
(CMH) targets mRNA of the c-FLIP variants and induces
apoptosis in MCF-7 human breast cancer cells. Mol Cell
Biochem 2010; 342: 133–42.
37. Safa AR, Day TW, Wu CH. Cellular FLICE-like in-
hibitory protein (C-FLIP): a novel target for cancer therapy.
Curr Cancer Drug Targets 2008; 8: 37–46.
38. Bagnoli M, Canevari S, Mezzanzanica D. Cellular
FLICE-inhibitory protein (c-FLIP) signalling: a key regula-
tor of receptor-mediated apoptosis in physiologic context and
in cancer. Int J Biochem Cell Biol 2010; 42: 210–3.
39. Chow VT, Lee SS. DENN, a novel human gene dif-
ferentially expressed in normal and neoplastic cells. DNA Seq
1996; 6: 263–73.
40. Kurada BR, Li LC, Mulherkar N, et al. MADD,
a splice variant of IG20, is indispensable for MAPK activation
and protection against apoptosis upon tumor necrosis factor-
alpha treatment. J Biol Chem 2009; 284: 13533–41.
41. Li LC, Sheng JR, Mulherkar N, et al. Regulation
of apoptosis and caspase-8 expression in neuroblastoma cells
by isoforms of the IG20 gene. Cancer Res 2008; 68: 7352–61.
42. Prabhakar BS, Mulherkar N, Prasad KV. Role
of IG20 splice variants in TRAIL resistance. Clin Cancer Res
2008; 14: 347–51.
43. Mulherkar N, Prasad KV, Prabhakar BS. MADD/
DENN splice variant of the IG20 gene is a negative regulator
of caspase-8 activation. Knockdown enhances TRAIL-induced
apoptosis of cancer cells. J Biol Chem 2007; 282: 11715–21.
44. Mulherkar N, Ramaswamy M, Mordi DC, Prab-
hakar BS. MADD/DENN splice variant of the IG20 gene
is necessary and sufficient for cancer cell survival. Oncogene
2006; 25: 6252–61.
45. Efimova EV, Al-Zoubi AM, Martinez O, et al. IG20,
in contrast to DENN-SV, (MADD splice variants) suppresses
tumor cell survival, and enhances their susceptibility to apop-
tosis and cancer drugs. Oncogene 2004; 23: 1076–87.
46. Niu Z, Jin W, Zhang L, Li X. Tumor suppressor
RBM5 directly interacts with the DExD/H-box protein
DHX15 and stimulates its helicase activity. FEBS Lett 2012;
586: 977–83.
47. Rintala-Maki ND, Sutherland LC. Identification and
characterisation of a novel antisense noncoding RNA from the
RBM5 gene locus. Gene 2009; 445: 7–16.
48. Kotlajich MV, Hertel KJ. Death by splicing: tumor
suppressor RBM5 freezes splice-site pairing. Mol Cell 2008;
32: 162–4.
49. Mathema VB, Koh YS. Inhibitor of growth-4 mediates
chromatin modification and has a suppressive effect on tu-
morigenesis and innate immunity. Tumour Biol 2012; 33: 1–7.
50. Zhu Z, Luo Z, Li Y, et al. Human inhibitor of growth
1 inhibits hepatoma cell growth and influences p53 stability
in a variant-dependent manner. Hepatology 2009; 49: 504–12.
51. Unoki M, Shen JC, Zheng ZM, Harris CC. Novel
splice variants of ING4 and their possible roles in the regulation
of cell growth and motility. J Biol Chem 2006; 281: 34677–86.
52. Yang X, Guo Z, Sun F, et al. Novel membrane-associ-
ated androgen receptor splice variant potentiates proliferative
and survival responses in prostate cancer cells. J Biol Chem
2011; 286: 36152–60.
53. Li J, Cao B, Liu X, et al. Berberine suppresses androgen
receptor signaling in prostate cancer. Mol Cancer Ther 2011;
10: 1346–56.
54. You Z, Dong Y, Kong X, et al. Differential expression
of IL-17RC isoforms in androgen-dependent and androgen-
independent prostate cancers. Neoplasia 2007; 9: 464–70.
55. Ratajska M, Antoszewska E, Piskorz A, et al. Cancer
predisposing BARD1 mutations in breast-ovarian cancer
families. Breast Cancer Res Treat 2012; 131: 89–97.
56. Feki A, Jefford CE, Berardi P, et al. BARD1 induces
apoptosis by catalysing phosphorylation of p53 by DNA-
damage response kinase. Oncogene 2005; 24: 3726–36.
57. Edmond V, Moysan E, Khochbin S, et al. Acetyla-
tion and phosphorylation of SRSF2 control cell fate decision
in response to cisplatin. EMBO J 2011; 30: 510–23.
58. Eckhart L, Henry M, Santos-Beneit AM, et al. Al-
ternative splicing of caspase-8 mRNA during differentiation
Experimental Oncology 34, 212–217, 2012 (September) 217
of human leukocytes. Biochem Biophys Res Commun 2001;
289: 777–81.
59. Hanoun N, Bureau C, Diab T, et al. The SV2 vari-
ant of KLF6 is down-regulated in hepatocellular carcinoma
and displays anti-proliferative and pro-apoptotic functions.
J Hepatol 2010; 53: 880–8.
60. DiFeo A, Martignetti JA, Narla G. The role
of KLF6 and its splice variants in cancer therapy. Drug Resist
Updat 2009; 12: 1–7.
61. Mallick S, Patil R, Gyanchandani R, et al. Human
oral cancers have altered expression of Bcl-2 family members
and increased expression of the antiapoptotic splice variant
of Mcl-1. J Pathol 2009; 217: 398–407.
62. Prinos P, Garneau D, Lucier JF, et al. Alternative
splicing of SYK regulates mitosis and cell survival. Nat Struct
Mol Biol 2011; 18: 673–9.
63. Goodman PA, Wood CM, Vassilev A, et al. Spleen
tyrosine kinase (Syk) deficiency in childhood pro-B cell acute
lymphoblastic leukemia. Oncogene 2001; 20: 3969–78.
64. Martin JA, Wang Z. Next-generation transcriptome
assembly. Nat Rev Genet 2011; 12: 671–82.
65. Ozsolak F, Milos PM. RNA sequencing: advances,
challenges and opportunities. Nat Rev Genet 2011; 12: 87–98.
66. de Almeida SF, Carmo-Fonseca M. Design principles
of interconnections between chromatin and pre-mRNA splic-
ing. Trends Biochem Sci 2012; 37: 248–53.
67. Gabut M, Samavarchi-Tehrani P, Wang X, et al.
An alternative splicing switch regulates embryonic stem cell
pluripotency and reprogramming. Cell 2011; 147: 132–46.
68. Busch A, Hertel KJ. Evolution of SR protein and
hnRNP splicing regulatory factors. Wiley Interdiscip Rev
RNA 2012; 3: 1–12.
69. Faber K, Glatting KH, Mueller PJ, et al. Genome-wide
prediction of splice-modifying SNPs in human genes using
a new analysis pipeline called AASsites. BMC Bioinformatics
2011; 12 (Suppl 4): S2.
70. Capriotti E, Altman RB. Improving the prediction
of disease-related variants using protein three-dimensional
structure. BMC Bioinformatics 2011; 12 (Suppl 4): S3.
71. Kole R, Krainer AR, Altman S. RNA therapeutics: be-
yond RNA interference and antisense oligonucleotides. Nat
Rev Drug Discov 2012; 11: 125–40.
Copyright © Experimental Oncology, 2012
|