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although extensive research has been done in the last 2 decades , the regulation of c - myc activation and c - myc - dependent signal transduction pathways has not yet been fully elucidated . in this article
we review current knowledge about htert transcription , which has been proved to be significantly up - regulated by c - myc , and , based on previous findings , we postulate that e2f1 , another c - myc - upregulated gene , may act as a negative regulator of htert expression for its function in repressing htert transcription .
the e2f1-mediated feedback inhibition of htert transcription , if existing , might be an important mechanism for normal cells to control the transmission of c - myc signals upon oncogenic stress .
as a transcription factor , the c - myc oncoprotein has been estimated to regulate up to 15% of all human genes .
these genes are essential to almost every aspect of cell behavior , including cell growth and proliferation , differentiation , and apoptosis . in light of these functions
, it is not surprising that the activation of c - myc and c - myc - mediated downstream signal transduction is tightly regulated in normal cells .
a great deal of recent work has determined that dysregulation of c - myc is closely associated with tumor initiation and progression .
supporting the role of c - myc in human tumors is the observation of sustained c - myc activation and its association with poor prognosis .
in addition , studies using transgenic mice , in which the c - myc oncogene is constitutively expressed in a given cell type by means of a tissue - specific promoter , have supported the view that c - myc activation , as an initial event , is important for the formation of certain tumors .
telomere maintenance by telomerase has been proposed as an essential prerequisite for cell immortalization and tumorigenesis .
human telomerase reverse transcriptase , htert , is the catalytic subunit of telomerase , and its upregulation is the rate - limiting step for telomerase activity .
given the fact that ectopic expression of htert leads to immortalization of many human somatic cells , it is almost inevitable that in normal cells the transcription of htert gene is tightly repressed . elevated expression of htert has been detected in over 85% of human tumors .
thus , the question emerged as to how the transcription of htert gene is triggered in the process of tumorigenesis . over the past 10 years
, mounting evidence indicates that upregulation of htert is one of the important links in c - myc signal transduction pathway .
the contribution of elevated c - myc activity to cell immortalization was already recognized nearly 30 years ago when c - myc was classified as an oncogenic protein that cooperated with ras to transform primary embryonic rat cells .
consistent with this , some years later htert was identified as a direct transcriptional target of c - myc , and the transcriptional induction is independent of additional protein synthesis .
this finding defines a pathway of oncogenic immortalization in which c - myc activation increases the expression of htert , and increased htert expression leads to cell immortalization .
e2f1 is also a transcription factor and displays multiple activities that could be involved in either suppressing or promoting tumor development . until now
, few cellular genes have been demonstrated to have such a dual role in tumorigenesis .
generally , e2f1 is required for cell proliferation , whose activation promotes cell proliferation and growth by binding to the promoter region of several genes , including those that are involved in cell cycle regulatory activities and dna replication , and due to this it is considered as an oncogene in tumor progression .
however , it is now clear that in normal cells elevated e2f1 expression participates in many aspects of the apoptotic process , either by acting alone or in cooperation with other factors , such as p53 , to protect against tumorigenesis in the face of oncogenic transformation .
furthermore , e2f1 has been determined to be able to suppress htert expression by directly binding to the htert promoter [ 1416 ] , indicating an additional mechanism for normal cells to control the activation of htert , in which e2f1 also functions as a tumor suppressor gene .
both c - myc and e2f1 are important regulators of cell signaling . it has been revealed that there is a close crosstalk between c - myc and e2f1 signaling pathway , which is believed to control cell fate decisions .
it is known with certainty that c - myc and e2f1 can activate each other s transcription , thereby establishing a positive feedback circuit . in the absence of additional regulatory mechanisms
, this circuit might be expected to overactivate both c - myc and e2f1 , leading to cellular confusion . obviously , this does not happen , indicating the possibility of another mechanism for regulation of c - myc and e2f1 interaction in cells .
recent evidence indicated that in noncancerous cells the mir-17 - 92 cluster is another important regulator involved in the c - myc and e2f1 networks [ 2022 ] .
e2f1 are inhibited at the post - transcriptional level by members of the mir-17 - 92 cluster such as mir-20a and mir-17 - 5p , while , as transcription factors , both c - myc and e2f1 can induce the expression of micrornas within the mir-17 - 92 cluster . since both mir-17 - 92 and e2f1 are transcriptionally activated by c - myc , this establishes an unusual network in which c - myc activates the transcription of e2f1 while simultaneously inhibiting its translation , suggesting that mir-17 - 92 is the negative control mechanism that prevents a runaway c - myc / e2f1 positive feedback . by using a mathematical model ,
it is additionally thought that the interactions between mir-17 - 92 and the transcription factors c -
myc and e2f1 might represent a molecular switch for cell proliferation and apoptosis via determining the levels of these 2 proteins .
besides the above description , because c - myc and e2f1 have some common regulatory properties in cell biology , including proliferation and apoptosis , it is also inevitable that there are other types of interaction between these 2 signal transduction pathways .
a study using k5 c - myc - transgenic mice showed that e2f1 is not required for proliferation , apoptosis , or tumorigenesis induced by c - myc .
however , inactivation of e2f1 was found to not only increase the incidence of tumor formation , but also to promote tumor initiation , indicating that e2f1 activation is a control mechanism serving to protect normal cells from the c - myc - induced tumorigenesis .
surprisingly , in this model system , inactivation of e2f1 increased the level of apoptosis induced by c - myc overexpression .
because the apoptotic process was not impaired in this model , the accelerated tumor progression caused by e2f1 inactivation can not result from the lack of e2f1-mediated apoptosis , suggesting that e2f1 has other functions to suppress the oncogenic transformation by c - myc .
observations that support this hypothesis also include : 1 ) c - myc - mediated proliferation and lymphomagenesis are compromised by e2f1 loss ; and 2 ) e2f1 blocks and c - myc accelerates hepatic ploidy and tumorigenesis in transgenic mouse models .
these results indicate that e2f1 can counteract c - myc oncogenic activation , especially in the process of tumor initiation .
in normal cells , the activity of c - myc is tightly controlled to maintain cellular homeostasis through multiple levels of regulation . in theory , as a transcription factor , oncogenic c - myc activation can regulate up to 15% of cellular genes .
however , only a fraction of these genes is responsive to c - myc activation in all cells analyzed , indicating the existence of some suppressors that function to limit the transcriptional function of c - myc .
interestingly , e2f1 is found to be able to bind the htert promoter and repress its expression .
therefore , these processes create a negative feedback loop that limits the c - myc - induced htert transcriptional expression .
e2f1 plays a dual role in signaling both cell proliferation and apoptosis , which is dependent on the expression level of the protein itself .
thus , it may be hypothesized that under mild c - myc activation , concomitant e2f1 upregulation could limit the expression of htert , which normally participates in the process of cell proliferation . whereas , under severe c - myc activation , the level of e2f1 protein is greatly increased , which leads to cell apoptosis ( figure 1 ) .
as noted above , mir-17 - 92 is within the regulatory loop between c - myc and e2f1 .
if mir-17 - 92 is significantly upregulated in response to c - myc activation , it can abrogate the increase in e2f1 expression induced by c - myc at the post - transcriptional level , and thus attenuate the inhibitory effect of e2f1 on the transcriptional expression of htert .
mutants of the htert promoter region might be another mechanism by which it can escape from the negative regulation of e2f1 .
overall , the inhibition of htert transcription by e2f1 might be an important mechanism for normal cells to counteract the oncogenic activity of c - myc .
if the negative regulating function of e2f1 is removed , htert is easily activated by oncogenic c - myc activation , and thereby results in cell immortalization and tumorigenesis .
precise regulation of c - myc and its signaling pathway is critical for cellular physiology , while its perturbations have detrimental consequences to cells and lead to various diseases , especially tumors . evidence from many studies clearly shows that c - myc - dependent htert transcription is a major mechanism for maintaining expression of telomerase and , apparently , contributes to tumor initiation .
however , not all increased c - myc expression in normal cells will result in activation of oncogenic sequences including htert .
e2f1 was determined to be transcriptionally activated by c - myc and has been shown to crosstalk extensively with c - myc signaling .
e2f1 was also found to be able to inhibit htert gene transcription [ 1416 ] .
therefore , we speculated that e2f1 may be a potential negative regulator of c - myc - induced htert activation , which exhibits a negative feedback regulation in normal cells upon c - myc oncogenic activation .
e2f1 has the ability to induce 2 seemingly contradictory processes of cell proliferation and apoptosis . under normal conditions ,
notably , e2f1-induced apoptosis has a physiological role and is not just an accidental result of ectopic expression .
we postulate that in normal cells an accompanying increase of e2f1 expression suppresses the c - myc - dependent htert transcription , and once the accompanying e2f1 expression had exceeded a certain threshold , cells enter spontaneously into apoptosis . at present , there are still no direct experimental data to support this hypothesis .
therefore , specific studies designed to provide information about the possible feedback regulation are needed .
also , the integration of the mir-17 - 92 cluster into the feedback regulation awaits further study and might prove to be a comprehensive mechanism to initiate tumorigenesis . since mutants of htert promoter region can make cells escape from the surveillance mediated by e2f1 , c - myc activation , even when the activation is mild , will lead to the transcriptional activation of htert and consequently lead to cell tumorigenesis under such conditions . because htert activation constitutes
a critical step in the process of tumorigenesis , a better understanding of htert regulation may provide not only a rationale for the molecular basis of tumor initiation , but also a path to the development of therapies based on the manipulation of htert activity . in this article , we postulate e2f1 as a negative regulator of c - myc - induced htert expression , and suggest possible explanations for ways by which cells escape this negative regulation .
if this hypothesis were confirmed , it would indicate several important molecular targets for cancer prevention .
summaryprevious studies have revealed that the link between c - myc and e2f1 pathway plays a pivotal role in regulating cell growth and death . 
 human telomerase reverse transcriptase ( htert ) , activation of which is required for cell immortalization and transformation , has been confirmed to be a direct transcriptional target of c - myc . 
 it is of note that e2f1 , which is also a direct transcriptional target of c - myc , can bind the htert promoter and repress its expression . 
 thus , although oncogene c - myc can be activated in normal cells , for the subsequent induction of e2f1 , it may still be insufficient to trigger the expression of htert . 
 this negative feedback regulation , if it exists , may be another mechanism for normal cells to control the transmission of c - myc - mediated oncogenic signals . in this article 
 , we reviewed current knowledge about the crosstalk among c - myc , e2f1 and htert , with an emphasis on the hypothesis that e2f1 negatively regulates c - myc - induced htert transcription . 
 additionally , we postulated that the mir-17 - 92 cluster - mediated regulation of c - myc and e2f1 expression may be of particular importance for the repression of htert transcription .