the e2f transcription factor is best known for its ability to regulate cell cycle progression by coordinating a large group of genes involved in g1-to - s phase transition . e2f
regulated genes include cell cycle regulators , such as cyclin eand cdc25a , and genes that encode essential components of the dna replication machinery . in agreement with the idea that e2f is an important regulator of cell proliferation , studies in several experimental systems
have shown that the ectopic expression of e2f is sufficient to drive quiescent cells into s phase , while the inhibition of e2f - dependent transcription blocks cell proliferation [ 24 ] .
e2f cell cycle activity is controlled through the temporally regulated physical association of pocket proteins .
the hypophosphorylated retinoblastoma protein prb represses e2f activity by shielding the e2f transactivation domain leading to restriction of cell cycle progression . during the course of cell cycle progression through the restriction point ,
prb becomes phosphorylated by the activity of cyclindependent kinases ( cdks ) resulting in the release of e2f , thereby causing its activation ( fig .
it is currently believed that most , and perhaps all , human cancers contain mutations that comprise prb function and that this contributes to their ability to proliferate in an environment that would cause normal cells to arrest . during transition of cells from g1 to s phase
, the activity of e2f is controlled by prb , which binds e2f / dp , leading to transcriptional repression of e2f - responsive promoters in go / g1 . in late g1 prb
is phosphorylated by cyclin - dependent kinases ( cdk ) , which results in the release of e2f .
free e2f transactivates growth promoting genes such as cyclin e or cdc25a , resulting in s phase entry and cell cycle progression .
e2f is a family composed of at least eight members that can be divided into distinct subgroups on the basis of their structural and functional similarities ( reviewed in ref . ) .
e2f1 , e2f2 and e2f3a are transcriptional activators , whereas e2f3b , e2f4 , e2f5 , e2f6 and e2f7 act as repressors of transcription .
the most recently identified e2f family member , e2f8 , resembles the organization of e2f7 in the presence of two separate dna - binding domains . like e2f7
all e2f proteins except e2f7 and e2f8 function in heterodimeric complexes with dp family ( dp1-dp4 ) proteins . from mutant mouse models it became clear that different e2f and dp subunits perform distinct , perhaps overlapping functions in the control of cell cycle progression , as well as unique roles during development , tissue homeostasis and apoptosis . for example , e2f3 is important for the control of cellular proliferation , while e2f4 and e2f5 are essential for g1 control and cell cycle exit as well as for normal mouse development .
previous studies suggest a role for e2f7 in facilitating cell cycle arrest in both g1 and g2 phases .
in contrast , e2f4 can associate with all pocket proteins , while e2f5 solely binds p130 .
e2f6 as well as the newest family members e2f7 and e2f8 lack a transactivation domain and do not interact with any pocket protein .
recent genomic studies have found that the function of the e2f transcriptional program extends further than the g1/s transition .
chromatin immunoprecipitation experiments [ 1013 ] , expression profiling studies [ 1417 ] and a recently performed proteomic analysis   showed that e2f proteins bind to and modulate expression of a large fraction of genes with diverse functions , suggesting a widespread role for e2f in the human genome .
currently , the best - characterized activity , especially at the hands of e2f1 , in addition to its traditional role in cell cycle progression is its ability to induce apoptosis [ 1922 ] . in some setting , another member of the e2f family , e2f3 , also induces apoptosis .
however , this e2f3-induced apoptosis was found to be e2f1-dependent and is largely attributed to the ability of e2f3 to transactivate the e2f1 gene , indicating that accumulation of crucial levels of e2f1 activity , and not total e2f activity , is essential for the induction of apoptosis .
a large number of studies clearly support the role of e2f1 as a tumour suppressor rather than an onco - gene [ 2426 ] . under deregulated conditions the activity of e2f1
is linked to events that determine cell fate through the induction of apoptosis , thus protecting the organism against oncogenic transformation .
mice , for example , lacking e2f1 ( e2f1 ) exhibit defects in apoptosis together with an increased incidence of tumour development [ 24 , 25 ] , and the level of apoptosis seen in rbmice is suppressed by e2f1 deficiency .
different mechanisms have been attributed to the ability of e2f1 to cause apoptosis , which can occur through both p53-dependent and independent path - ways ( fig .
, p53 accumulates following e2f1 expression   through activation of the cdkn2a transcript p14arf , which in turn interacts with mdm2 , thereby preventing mdm2 from targeting p53 for ubiquitination and sub - sequent degradation . lately
, additional arf - independent pathways have been described , and some reports even imply a negative feedback by arf since over - expression of arf inhibits e2f1-dependent apoptosis , and targets e2f1 for proteasomal degradation .
e2f1-induced apoptosis in the absence of arf was shown to correlate with p53 phosphorylation at residues that are also phosphory - lated in response to dna damage [ 29 , 31 ] .
moreover , induction of both apoptosis and p53 phosphorylation by e2f1 are abolished by the atm and atr protein kinase inhibitor caffeine , supporting that e2f1 uses the atm signalling pathway to induce p53 and chk2 phosphorylation and thereby apoptosis [ 32 , 33 ] .
correspondingly , it was reported that the e2f1 transcription factor elevates atm promoter activity by direct binding , which is accompanied by enhanced p53 phosphorylation .
in addition , e2f1 interacts directly with p53 via the cyclin a  binding domain of e2f1 , and this interaction enhances p53 apoptotic activity in response to dna damage
e2f1 promotes apoptosis via the tumour suppressor p53 and independent of p53 . in the p53-dependent pathway ,
e2f1 activates arf , which in turn stabilizes p53 by alleviating its proteosome degradation through mdm2 .
arf negatively regulates e2f1 in a feedback loop mechanism . in response to dna damage e2f1
is stabilized through phosphorylation by atm / atr and chk2 kinases ( chk2 also stabilizes p53 by phosphorylation ) .
in addition , e2f1 interacts directly with p53 via the cyclin a binding domain , thereby inducing p53-mediated apoptosis . alternatively ,
p53-independent apoptosis by e2f1 occurs via direct up - regulation of genes including p73 and apaf-1 .
the assembly of apaf1 with cytochrome c released from the mitochondria leads to formation of the apoptosome that catalyzes caspase-9 , and successive initiation of proapoptotic effector caspases including caspase-3 .
e2f1-induced apoptosis occurs also independent of p53 in tissue culture and transgenic mice [ 3638 ] , and prb has been shown to protect p53-null cells from apoptosis in an e2f1-binding  dependent manner .
apoptotic targets of e2f1 in the absence of p53 include the p53 homolog protein p73 [ 40 , 41 ] and apoptosis protease - activating factor 1 ( apaf1 )   both of which are transcriptionally regulated by e2f1 .
this initiates the assembly of apaf1 with cytochrome c followed by procaspase-9 activation and successive initiation of proapoptotic effector caspases including caspase-3 , -6 and -7 .
mapping studies revealed that the apoptotic ability of e2f1 requires the dna - binding domain but not its transactivation function , since mutants of e2f1 that lack the transactivation domain are still able to induce cell death [ 36 , 37 , 43 ] .
from these experiments , it was supposed that proapoptotic e2f1 target genes are activated by removal of e2f1/rb repression rather than direct transactivation . moreover , bell et al . recently reported dna - binding  independent cell death from a minimal proapoptotic region of e2f1 that is consequently unable to transactivate , repress or derepress e2f target genes .
however , since this activity is also present in e2f2 and e2f3 proteins , it might therefore define a distinct mechanism of death by e2f proteins . because normal cells proliferate without suffering e2f1-induced apoptosis , its proapoptotic potential
integration of external signals appears to play an important role in determining the sensitivity to e2f1-induced apoptosis .
for example , cell survival signals via the pi3/akt and the egfr / ras / raf pathway have been shown to promote e2f1-driven cell proliferation by suppressing e2f1-induced apoptosis [ 4547 ] .
in addition , dna damage signals have been suggested to specifically activate e2f1-dependent transcription of proapoptotic genes [ 4850 ] .
these changes stabilize e2f1 , increase its transactivation potential and allow it to preferentially bind the promoters of some proapoptotic genes .
overall , the final decision of whether e2f1 leads to cell proliferation or apoptosis might thus depend on the genetic status or molecular back - ground of the cell .
this means that e2f1 would function strictly as a growth promoter if pathways that mediate e2f1-induced apoptosis are disabled .
many of the drugs cause dna damage and the inflicted dna damage activates apoptotic programs that lead to cell death . forced expression of e2f1 has been shown to sensitize tumour cells to the proapoptotic signals generated by chemotherapeutic drugs or ionizing radiation [ 5156 ] .
in addition , endogenous e2f1 is up - regulated after dna damage in a manner analogous to that of p53 , suggesting its direct role in responsiveness to conventional genotoxic stress signals . in response to dna damage , the e2f1 protein
is stabilized through distinct mechanisms , including direct phosphorylation by the ataxia - telangiectasia mutated ( atm ) kinase , the atm and rad3-related ( atr ) kinase and the chk2 kinase [ 32 , 48 , 58 ] , and also by acetylation through p300/creb - binding protein - associated factor ( p / caf ) .
activation of the atm dna damage response pathway is commonly observed in a variety of early - stage tumours , suggesting that this checkpoint response functions to suppress the development of cancer .
has demonstrated that e2f1 is a critical determinant of the cellular response in cancer cells to genotoxic stress .
taking advantage of drosophila ddp and de2f1;de2f2 mutant animals , it was shown that the role of de2f1 within individual developing wing discs exposed to -irradiation is completely context - dependent .
de2f1/ddp appears to protect non - proliferating cells and sensitizes proliferating cells to -irradiation - induced apoptosis .
the loss of the prb - dependent cell cycle checkpoint might allow cancer cells to enter s phase and initiate apoptosis under conditions where normal cells would undergo a g1 arrest and initiate dna repair .
in addition , e2f can increase the effectiveness of chemotherapeutic agents that are most active in s phase cells and/or that require the presence of a particular cell cycle  dependent target for the induction of cell death [ 60 , 61 ] .
the frequent deregulation of e2f1 in human tumours , taken together with its apoptotic potential and its stabilization after damage suggest that e2f1 may play an important role in the enhanced sensitivity of tumour cells to dna damage - induced cell death . in agreement with this , increased levels of proapoptotic target genes of e2f1 such as adenoviral e1a and p73 have been invoked as a potential basis for selective killing of cancer cells , including p53-defective tumour cells , by dna - damaging agents relative to normal cells [ 6264 ] .
in the past few years , a large number of novel e2f1-regulated target genes or gene networks functioning in the apoptotic program have been identified . from these studies
it becomes evidently clear that e2f1 is a key regulator of the apoptotic machinery by being involved in many aspects of programmed cell death , both by activating proapoptotic genes and through the inhibition of antiapoptotic survival signals .
e2f1 induces the expression of the proapoptotic bcl-2 homology 3 ( bh3)-only proteins puma , noxa , bim , hrk / dp5 and bik in cancer cells through a direct transcriptional mechanism [ 65 , 66 ] .
in fact , e2f1 binds to the promoters of these genes and transactivates them by a p53-independent mechanism .
bh3-only proteins are members of the bcl-2 protein family and are required for the execution of apoptotic cell death by integrating diverse apoptotic stimuli into a common death pathway governed by other multidomain bcl-2 family members . while some bh3-only proteins , such as bid , may chaperone the activation of bax and bak at the mitochondrial membrane , most others antagonize the functions of the anti - apoptotic bcl-2 family members .
reversely , reducing the expression of noxa and puma by rna interference diminished apoptosis induced by e2f1 . like e2f1 itself ,
some of these proteins , for example , bik and puma are also up - regulated in response to chemotherapeutic agents [ 65 , 66 ] .
consistent with their responsiveness to e2f1 , it has been shown that the dna damage - induced elevation of puma and bik is abolished by suppression of e2f1 activity , indicating that both pathways contribute to the apoptotic response to damaging agents .
increased expression of proapoptotic bcl-2 genes including bad , bak and bid after e2f1 activation in p53-deficient tumour cells was also reported in a gene array analysis by stanelle et al .. in the same study , kiaa0767 , termed d(eath)-i(nducing)-p(rotein ) , was identified as a relevant apoptotic target of e2f1 .
the dip protein is localized in the mitochondria and mediates e2f1-induced apoptosis independently of p53 in a partially caspase - independent manner . in addition
, transcriptional activation of the second mitochondrial activator of caspases or direct inhibitor - of - apoptosis - binding protein with low pi ( smac / diablo ) was reported as a mechanism by which e2f1 promotes p53-independent apoptosis via the mitochondria .
these proteases are synthesized as inactive proenzymes and processed to an active state during apoptotic cell death .
initiator caspases ( caspase-2 , -8 and -9 ) trigger a cascade that result in the activation of effector caspases ( caspase-3 and -7 ) , which in turn produce the characteristic morpho - logical changes associated with apoptosis . enforced e2f1 expression has been shown to result in the accumulation of caspase-2 , -3 , -7 , -8 and -9 through a direct transcriptional mechanism .
e2f1 can facilitate caspase activation through p53-dependent signals , resulting in mitochondrial release of cytochrome c , while simultaneously increasing caspase expression through direct caspase promoter binding that is independent of p53 . by up - regulation of caspases ,
particularly caspase-8 , e2f1 might sensitize cells to death - inducing ligands such as tumour necrosis factor ( tnf ) .
another novel death effector protein of e2f1 is siva , which was identified to be directly up - regulated by e2f1 and p53 via their corresponding consensus sites in the siva promoter .
siva is a proapoptotic protein containing a death domain that is expressed on a broad scope of tissues , including cells of the immune system and the cns as well as tumour cells . as a potential mechanism for apoptosis induction by siva
, its interaction with members of the tnf - receptor family and antiapoptotic bcl-2 family members has been considered .
these studies suggest that siva may function through multiple mechanisms possibly dependent on the cell type and apoptotic stimulus .
in addition to the findings by fortin et al . indicating that the siva gene exhibits a striking induction during p53-mediated neuronal apoptosis , up - regulation of siva was also observed in p53-deficient hepatoma cells in response to cisplatinum - induced apoptosis , suggesting that it is also regulated in a p53-independent manner , perhaps by e2f1 .
some clarity has been shed on the requirement of the ask1-p38 mapk pathway for e2f1-induced apoptosis .
the ginsberg group   showed that e2f1 modulates the activity of the p38 mapk path - way through up - regulation of p38 mapk phosphorylation .
this involves transcriptional induction of the ask1 ( apoptosis signal - regulating kinase 1 ) gene ( also known as map3k5 ) , a member of the mitogen - activated protein kinase family that phosphorylates p38 mkks .
dna microarray analysis revealed map3k5 up - regulation following e2f1 over - expression in p53-positive u-2os osteosarcoma   and in p53-deficient melanoma cells .
for example , map3k5 has been shown to mediate rapamycin - induced apoptosis via phosphorylation of c - jun in p53-negative mouse embryonic fibroblasts , whereas suppression of kinase activity and ask1-jnk signalling through the interaction of ask1 with p21cip1 in p53 wild - type cells   leads to apoptosis inhibition .
the relevance of the ask1-p38 connection for e2f1-induced apoptosis is also evidently clear from data demonstrating that e2f1 regulates the activity of the p38 signalling inhibitor wip1 .
further insight into the mechanism by which e2f1 directs p53 activity towards apoptosis comes from studies showing that e2f1 up - regulates the expression of proapoptotic cofactors of p53 , jmy , tp53inp1 and the apoptosis - stimulating proteins of p53 ( aspp ) family members aspp1 and aspp2 by a direct transcriptional mechanism [ 80 , 81 ] . tp53inp1 was shown to mediate phosphorylation of p53 on serine 46 .
both aspp proteins modulate the cellular apoptotic threshold by direct interaction with p53 , thereby enhancing the dna binding and trans - activation function of p53 on the promoters of proapoptotic genes in vivo .
herein , aspp specifically renders p53-guided apoptosis by stimulation of the p53-regulated promoters bax and pig-3 .
while these studies provide additional pathways by which e2f1 cooperates with p53 to induce apoptosis , the aspp promoters can also be transactivated by e2f1 in a p53-deficient context as shown by chip   and reporter gene assays [ 80 , 83 ] .
since aspp1 and aspp2 are specific activators of the apoptotic function of all p53 family members , e2f1 may use this pathway to increase the apoptotic function of p63 and p73 independently of p53 .
this ambivalence seems to be a common concept for death proteins since it has also been observed for other apoptosis factors such as siva and map3k5 .
siva seems to link the e2f / arf / p53- and the p53-independent apoptotic pathway . in a functional so - called technical knockout approach using the saos-2 er - e2f1 cell line , where e2f1 activity can be conditionally induced on 4-hydroxytamoxifen treatment , several other potential death targets of e2f1 were identified such as galectin-1 ( or lgals1 ) .
e2f1-induced apoptosis was significantly abolished when galectin-1 anti - sense cdna was introduced into p53-negative cells .
galectin-1 has been shown to play a key role in tumour - immune escape by killing antitumour effector t cells .
it sensitizes , for example , human - resting t cells to fas ( cd95)/caspase-8mediated cell death .
e2f1 was earlier shown to be essential for t - cell apoptosis by a process called t - cell receptor ( tcr ) activation - induced cell death ( aicd ) .
lissy et al . demonstrated that t cells were protected from tcr - mediated apoptosis by disruption of the e2f1 gene or p73 .
together these findings support a function for e2f1 in balancing life and death of immune effector cells .
beside direct activation of various apoptosis - related genes described earlier , a second major mechanism by which e2f1 sensitizes cells to apoptosis is via inhibition of antiapoptotic signalling .
one example is the inhibition of nf-b that functions in most cases as a survival signal .
activation of tnfr in response to tnf results in the stimulation of nf-b via traf2 , which contributes to the inhibition of cell death .
importantly , e2f1 expression sensitizes cells to apoptosis by down - regulation of traf2 protein levels , thereby inhibiting antiapoptotic nf-b signalling .
the general principle of blocking survival factors by e2f1 to induce apoptosis is supported by the data from two other studies [ 89 , 90 ] .
they reported that over - expression of e2f1 suppresses the expression of the apoptotic antagonists bcl-2 and its family member mcl-1 which leads to apoptosis . in both cases ,
the e2f1-induced decrease in bcl-2 and mcl-1 levels occurs independently of the arf / p53 pathway .
this scenario renders cells susceptible to apoptosis by altering the balance between anti- and proapoptotic bcl-2 family members in favour of those that induce cell death . together with the induction of bh3-only proteins and other proapoptotic bcl-2 family members by e2f1
there is increasing evidence that execution of the apoptotic program is achieved by an intense cross - talk between the mitochondria and the endoplasmic reticulum ( er ) ( reviewed in ref . ) .
a number of molecules involved in mitochondrial apoptosis are also involved in er stress - induced cell death , suggesting that the er might regulate apoptosis by sensitizing the mitochondria by a number of extrinsic and intrinsic stimuli , as well as by inducing apoptosis .
bcl-2 family members , for example , localize to the er membrane , thereby disrupting er homeostasis by altering er membrane permeability as a result of mitochondrial dysfunction .
unfolded protein response  mediated cell survival or cell death is regulated by the balance between the er chaperones grp78 and gadd153 .
e2f1 can down - regulate the expression of grp78 ( also known as bip ) , which normally protects cells from death induced by disturbance of er homeostasis [ 94 , 95 ] .
moreover , expression of another er chaperon , the 94 kd glucose - regulated protein ( grp94 ) , shown to be significantly up - regulated in human esophageal cancers , is also inhibited by e2f1 . from these data
it is evident that e2f1-mediated apoptosis involves both mitochondrial and er - related death pathways .
e2f1 sensitizes cells to apoptosis by both direct activation of proapoptotic genes and through inhibition of antiapoptotic survival genes , thereby engaging different death signalling pathways via the mito - chondria ( intrinsic ) , death receptors ( extrinsic ) and the endoplasmic reticulum .
since apoptosis programs can be manipulated to produce massive changes in cell death , the genes and proteins controlling apoptosis are potential drug targets . as indicated earlier , acquired apoptotic defects during cancer progression involve three types of molecular changes : ( i ) inactivation of proapoptotic effectors , for example , p53 or apaf-1 ; ( ii ) activation of antiapoptotic factors , for example , bcl-2 and ( iii ) reinforcement of survival signals .
thus , anti - cancer studies set out to either boost cell death or to impede antiapoptotic and proliferative pathways .
two observations suggest that such strategies are feasible . first , most antiapoptotic mutations act relatively upstream in the program implying that tumour cells generally retain the machinery and latent potential for apoptosis .
second , tumour - specific alterations in apoptotic programs provide opportunities to target cell death in a selective manner .
restoration of the apoptotic pathway , for example , by re - introduction of p53   or activation of apaf-1   has been shown to increase the sensitivity of neoplastic cells to dna - damaging agents .
the inef - fectiveness of a p53-based gene therapeutic strategy in certain conditions is , however , problematic ( e.g. mutant p53 in tumour cells trans - dominantly impairs the function of wild - type p53 ) . here , genes ( such as proapoptotic e2f1 targets ) are particularly useful that compensate or bypass cell death defects regardless of the p53 status . in the past few years , pre - clinical experiments mainly using e2f1 itself as anti - cancer therapeutic have been initiated . the effect of e2f1 over - expression on tumour growth has been evaluated in several types of human cancer in vitro and in vivo including glioma , melanoma , esophageal cancer , breast- and ovarian carcinoma , head and neck squamous cell cancer , gastric cancer ; pancreatic carcinoma and nonsmall - cell lung cancer [ 54 , 100108 ] .
these studies clearly indicate that apoptosis induction by adenoviral expressed e2f1 results in growth suppression and increased responsiveness of tumour cells to chemotherapy with relative sparing of normal tissues
. this selectivity might be due to the fact that normal cells contain wild - type prb , which likely can bind to and antagonize the activity of exogenous e2f1 .
furthermore , transcription from e2f1-responsive promoters is higher in cancer cells than in normal cells .
however , targeting e2f1 itself is a cumbersome mission possibly feasible for some but not suitable for all therapeutic purposes because of its dual role in cell cycle progression and apoptosis . regarding this issue
, it has been shown that a transcriptionally inactive form of e2f1 is able to induce apoptosis without activating proliferation in human coronary vascular smooth muscle cells ( vsmc ) .
therefore , this strategy has widespread potential for preventing hyperproliferation in artherosclerosis , hypertension and restenosis after injury .
in addition to e2f1 , its downsteam target p73 was proven to be a valuable candidate for cancer therapy in tumour cells .
infection with an adenoviral vector encoding the beta isoform of p73 resulted in potent cytotoxicity based on a combination of cell cycle arrest and apoptosis induction [ 64 , 109 , 110 ] .
similar to e2f1 , p73 can efficiently induce apoptosis and enhanced chemosensitivity of tumour cells primarily resistant to wild - type p53 .
although this strategy warrants further consideration , the antitumoural effect exhibited by over - expression of p73 , in contrast to its homolog p53 , is not restricted to tumour cells .
although present data provide compelling evidence that effectors of e2f1-induced apoptosis can significantly kill cancer cells , their role as a target for cancer treatment is only beginning to emerge .
so far , in clinical studies antiapoptotic e2f1 regulated genes were used to hamper tumour growth instead of using approaches for introducing proapoptotic molecules .
antiapoptotic bcl-2 , for example , has been targeted extensively by antisense oligonucleotide approaches which interfere with bcl-2 activity , resulting in less bcl-2 expression and elevated levels of apoptosis . in the phase i  ii study ,
bcl-2 antisense oligonucleotide ( g3139 ) treatment of chemoresistant melanoma patients led to minor to complete therapeutic response in 6 of 14 cases when the antisense therapy was combined with dacarbazine administration . in a phase ii study , bcl-2 antisense oligonucleotide treatment of patients with multiple myeloma led to therapeutic responses in 55% of cases when combined with chemotherapy .
these data underline that inhibition of antiapoptotic bcl-2 is surely a promising treatment for otherwise resistant tumour entities .
 abstractdefects in apoptotic programs contribute to a number of human diseases , ranging from neurodegenerative disorders to malignancy , and treatment failure . 
 the genetic basis for apoptosis implies that cell death can be disrupted by mutations , raising the intriguing possibility that cell numbers can be regulated by factors that influence cell survival . 
 it is well documented that the e2f1 transcription factor is a key regulator of apoptotic programs . 
 e2f1-induced cell death occurs via multiple pathways , some of which involve the tumour suppressor p53 , and autonomous of p53 . 
 this has led to the opinion that e2f1 functions as a tumour surveillance factor , detecting aberrant proliferation and engaging apoptotic pathways to protect the organism from developing tumours . 
 frequently , novel players are discovered that expand the interpretation of apoptosis control by e2f1 . 
 this information will help to produce new strategies to exploit e2f1-induced apoptosis for therapeutic benefit . 
Introduction
Molecular mechanisms of E2F1-induced apoptosis
E2F1 sensitizes tumour cells to DNA damage
E2F1 guided death pathways in cancer
Activation of proapoptotic genes
Inhibition of survival signalling pathways
E2F1 apoptosis and new therapeutic strategies