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Evolving intricacies and implications of E2F1 regulation

Rush Cancer, Institute Section of Myeloid Diseases and MDS Center, Rush-Presbyterian-St. Luke’s Medical Center, Rush University, Chicago, Illinois, USA

¹Correspondence: Departments of Medicine and Biochemistry, Rush University, 2242 West Harrison St., Suite 108, Chicago, IL 60612, USA. E-mail: suneelmundle{at}hotmail.com

	ABSTRACT

TOP ABSTRACT INTRODUCTION TRANSCRIPTIONAL REGULATION BY... E2F INTERPLAY AND... REGULATION OF E2F ACTIVITY:... REGULATION OF E2F1 AVAILABILITY,... CLINICAL IMPLICATIONS OF THE... REFERENCES

 
E2F transcription factors may play a pivotal role in the transcriptional regulation of several cellular processes far beyond the originally described cell cycle and proliferation. Among the six E2F family members, only E2F1 is noted for its role in apoptosis. The pocket protein family members Rb, p107, and p130 act as the main regulators of E2F activity. Nonetheless, in recent years other protein–protein interactions have been described for E2Fs. The post-translational modifications resulting from such protein interactions may have significant implications in the stability, half-life, and functional activity of E2Fs. In human diseases the significance of E2Fs is still under appreciated and is primarily recognized only as a consequence of the impairment in retinoblastoma gene product (Rb). However, with increasing knowledge of other protein interactions, the derailment of E2F activity could be anticipated to stem from an abnormality of any node in the complex network governing their availability and activity. The present review is intended to provide a perspective on the diversity of biochemical mechanisms underlying abnormal E2F expression and activity, understanding of which may have significant clinical implications.—Mundle, S. D., Saberwal, G. Evolving intricacies and implications of E2F1 regulation.

Key Words: E2F • post-translational modifications • pocket proteins

	INTRODUCTION

TOP ABSTRACT INTRODUCTION TRANSCRIPTIONAL REGULATION BY... E2F INTERPLAY AND... REGULATION OF E2F ACTIVITY:... REGULATION OF E2F1 AVAILABILITY,... CLINICAL IMPLICATIONS OF THE... REFERENCES

 
At the turn of the millennium, transcription factors have emerged as the major terminal nodes of intracellular signaling network that elicit eventual gene response. Among the members of this class of proteins, the E2F1 transcription factor originally isolated as the cellular mediator of the effects of adenovirus E1A oncogene (1) is of special interest because of its contrasting behavior under different circumstances involving cellular fates that are poles apart (2) . E2F1 belongs to a family of five additional homologues (E2F-2, -3, -4, -5, and -6) and two heterodimeric DNA binding protein partners called DP1 and DP2/3 (2 , 3) . These factors, as initially perceived to be the crucial regulators of cell cycle and proliferation, exhibit an interesting interplay among the family members in terms of their concentration, localization, and activity that results in a tight transcriptional regulation. These factors could be broadly divided into two classes: activators (E2F1, E2F2, and E2F3) and repressors (E2F4 and E2F5) of transcription. A survey of several reports (2 3 4 5 6 7) has highlighted important differences between these two classes of E2Fs, as outlined in Table 1 . E2F6, which lacks the cyclin and pRb regulatory domains as well as the trans-activation domain of E2F, continues to be viewed independent of the two classes mentioned above and as a repressor of E2F-dependent transcription (2) .

	TRANSCRIPTIONAL REGULATION BY E2FS

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The E2F family members have primarily been recognized for their pivotal role in cell cycle progression. It has now become clear that their spectrum of transcriptional control may span well beyond the set of genes related to the G1/S transition point of the cell cycle. The additional transcriptional targets of the E2F family that have largely been identified by using microarray technology or by computer-assisted identification of consensus E2F recognition promoter sequences include genes involved in mitosis, chromosome segregation, mitotic spindle checkpoints, DNA repair, chromatin assembly/condensation, apoptosis, differentiation, and development, etc. (8 9 10 11 12 13) . An elegant study by Müller et al. (13) using state-of-the-art techniques has revealed that E2F may influence the expression of 1240 of the total of 19,000 genes investigated in a single cell type, U2OS, although many of these genes still are regarded as expressed sequence tags and are yet to be named. Clearly however, the transcriptional regulation by E2Fs is more divergent than previously thought. The well-characterized E2F-responsive genes could be classified into three categories, as shown in Table 2 . The role of E2Fs in the regulation of these genes is either direct active induction, derepression, or active repression respectively (2 , 13 , 14) . A mutation in the E2F binding site in the promoter of some genes like dihydrofolate reductase or thymidine kinase prevents their activation at the G₁/S transition point in the cell cycle (15) . These genes are positively regulated by free activating E2Fs. As described later, in quiescent cells such genes may be repressed by the repressive E2Fs; upon stimulation, the transcriptional activation may occur in two steps where phosphorylation of p130 may cause the release of repressive E2Fs, followed by an immediate replacement of the E2F binding sites with free activating E2Fs that eventually induce transcription. In contrast, there are some genes like B-myb, cyclin E, or E2F1 where a mutation in the E2F binding sites causes their elevated expression prematurely during G₀/G₁ phase (2 , 15) . Such transcriptional repression is thought to be exercised by the pocket protein recruited by E2F and may require a corepressor that could bind to a promoter region, called cell cycle gene homology region or CHR contiguous to the E2F binding sites in the target genes (15) . The exact mechanism of derepression continues to be enigmatic. It appears that during transcriptional activation via derepression of these genes, the E2F binding sites could be unoccupied (16) . Conversely, the only well-recognized genes that are actively repressed by E2F1 independent of its pocket protein partner are plasminogen activator inhibitor 1 (PAI1) and connective tissue growth factor (13 , 14) . As demonstrated by Müller et al. (13) , the repression of these genes by E2F1 may require protein synthesis, indicating that the E2F1–3 may bring about repression of these genes by involving additional corepressor or via an independent transcriptional repressor, both of which remain unidentified at the present time.

Studies of E2F knockout mice have revealed that abolishment of the induction of proliferation of mouse embryonic fibroblasts requires a lack of all the three activating E2Fs: E2F-1, -2, and -3 (7) . The absence of either alone is not sufficient for a total proliferation block, thus suggesting a functional redundancy in proliferation control within the subfamily of transcriptional activator E2Fs. Although it was well known that among the activating E2Fs, E2F1 demonstrated the maximum potential for activating the reporter gene, it has only recently come to light that it may actually regulate a few genes independent of E2F2 and/or E2F3 (13) . Furthermore, these studies showed that similar target gene specificity is also likely for E2F2 and -3. These differences may offer a relative upper hand in transcriptional control of individual cellular processes involving E2Fs. Indeed, recent studies suggest that of the three activating E2Fs, E2F3 may serve as a rate-limiting factor and be critical for G₁/S transition (7 , 17 , 18) . Although the ability of inducing apoptosis appears to be a specific property of E2F1 only (19 20 21 22) , E2F3 has also been indicated to steer apoptosis (23) . A consensus is seen in that the tumor suppression is a specific property of E2F1 and not E2F3 (18 , 23 , 24) . The physiologic significance of the redundant vs. specific properties of the three activating E2Fs thus needs extensive investigation.

	E2F INTERPLAY AND TRANSCRIPTIONAL CONTROL

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It appears that some of the E2F-responsive gene promoters are repressed by the binding of E2F4–5/p130 complexes during cellular quiescence. At the G1/S transition point, E2F4–5 complexes are translocated from nucleus to cytoplasm; on the other hand, the E2F binding sites are occupied by the newly emergent E2F1–3/pRb complexes (25 , 26) . Subsequently, upon dissociation of the E2F component after phosphorylation of pRb, activation of these genes occurs under E2F control (2 , 7 , 27 , 28) . From mid- to late S/G₂ phase, the major complex seen is E2F4/p107, which is proposed to be cytoplasmic (2) . The subsequent complex that occupies the E2F recognition sites in the nucleus then must be E2F4/p130, perhaps restoring repression in order to maintain tight control over gene transcription (26) . Such interplay among the E2F family members, as well as between E2Fs and pocket proteins, must provide for the necessary leverage to regulate multiple processes like proliferation and differentiation. In a recent study by Fajas et al. (29) , it has been shown that E2F1-induced transcriptional activation stimulates adipocyte proliferation and clonal expansion, whereas subsequent E2F4-imposed transcriptional repression causes terminal differentiation. These findings may provide some mechanistic insight in understanding the counterintuitive presence of E2F binding sites in the promoters of genes involved in processes besides proliferation as described above.

	REGULATION OF E2F ACTIVITY: IMPORTANCE OF PROTEIN–PROTEIN INTERACTIONS

TOP ABSTRACT INTRODUCTION TRANSCRIPTIONAL REGULATION BY... E2F INTERPLAY AND... REGULATION OF E2F ACTIVITY:... REGULATION OF E2F1 AVAILABILITY,... CLINICAL IMPLICATIONS OF THE... REFERENCES

 
Involvement of the multifaceted E2F activity in diverse cellular processes would necessitate a stringent regulation of the dynamics of E2Fs. The research in the regulation of E2F activity is still in its infancy, and the majority of insights have been gained by experimental protein (over) expression or gene knockout techniques. Hence, it is hard to state the exact physiological relevance of these findings. However, these valuable observations may help in building a model of a regulatory cascade that may govern the availability, stability, and activity of E2Fs. At a genetic level, mutations or gene amplification in the family of E2Fs are almost unknown; hence, in disease conditions abnormal E2F activity is a consequence of dysregulation of other interacting proteins, primarily the pocket proteins.

The next level of regulation lies in induction, concentration, and localization of E2Fs. Whereas the repressive E2Fs are expressed constitutively, the activating E2Fs are induced just before the G₁/S transition point during cell cycle. E2Fs, like many other transcription factors manifest several protein–protein interactions. As described later, although the family of pocket proteins (pRb, p107, and 130) has been thought to be the major E2F complexing cellular components, it is now evident that many other protein–protein interactions may play an exceedingly important role in determining the availability, stability, and activity of E2Fs. The most well-investigated member of E2F family in this regard is E2F1.

The importance of abnormal and untimely E2F1 activity has so far been recognized only as an inevitable outcome of the process disabling pRb due to viral interference or genetic mutation. However, since E2F1 interacts with several other proteins and potentially could undergo numerous types of post-translational modifications, possibilities besides pRb could take equal precedence in shifting gears of E2F1 activity driving the cell into a variety of derailments. Besides functionally inactivating E2F1, binding to pRb offers protection from its degradation. Apparently since the pRb binding site is juxtaposed with the degradation flag p14^ARF binding site in the carboxyl-terminal region of E2F1, the binding of pRb would sterically hinder with p14^ARF binding and prevent E2F1 degradation (Fig. 1 ). Thus, after dissociation from pRb, the other protein interactions that result in various post-translational modifications of free E2F1 may be extremely vital for stability during its transcriptional activity.

View larger version (19K): [in this window] [in a new window]   Figure 1. Schema of distinct domains of E2F1 involved in its regulation (cyclin A binding and Rb binding), activity (DNA binding and transcriptional trans-activation) and degradation (p14ARF binding). The homo-hetero dimerization domain is usually engaged in forming a dimer with DP1. Note the proximity of pRb binding domain with the p14ARF binding region. The physical binding of pRb thus provides protection from degradation of E2F1.

	REGULATION OF E2F1 AVAILABILITY, ACCUMULATION, AND ACTIVITY

TOP ABSTRACT INTRODUCTION TRANSCRIPTIONAL REGULATION BY... E2F INTERPLAY AND... REGULATION OF E2F ACTIVITY:... REGULATION OF E2F1 AVAILABILITY,... CLINICAL IMPLICATIONS OF THE... REFERENCES

 
The hypophosphorylated Rb (pRb) is established as the most crucial regulator of E2F1 activity and the complex acts as an active transcriptional repressor. A sequential phosphorylation by cyclin-dependent kinases (cdks) is thus required to abrogate such transcriptional repression and release free E2F1 (30 31 32) . In mid-late G₁ phase of the cell cycle, cyclin D-cyclin dependent kinase 4/6 (cyclin D-cdk4/6) and cyclin E-cdk2 complexes have been demonstrated to hyperphosphorylate Rb (ppRb) in a stepwise manner (Fig. 2 A), finally causing its complete dissociation from E2F1 (32) . As recently reviewed by Trimarchi and Lees (3) , histone deacetylases (HDAC) and a methyltransferase (Suv39H1) associated with pRb that cause chromatin remodeling may play a significant role in the repressive function of pRb. The initial phosphorylation of pRb in its carboxyl-terminal region by cyclin D-cdk4/6 releases HDAC activity from the LXCXE binding sites in domain B of the Rb pocket and ablates the repressive action of pRb, but does not affect its E2F binding. Besides dissociating HDAC, carboxyl-terminal phosphorylation by cdk4/6 releases the steric constraint and thus promotes the binding of cyclin E-cdk2 to subsequently act on the Rb pocket. The relief from steric constraint on carboxyl-terminal region makes the S-567 phosphoacceptor site in the Rb pocket accessible to cdk2 phosphorylation, resulting in its complete dissociation from E2F1 (32) . Recent studies have demonstrated that cyclin D-cdk 4 may also phosphorylate E2F1 itself at serine-332 and -337 residues, further ensuring that irrespective of its phosphorylation status, Rb would not bind to E2F1 (33) .

View larger version (29K): [in this window] [in a new window]   Figure 2. Post-translational modifications of E2F1. A) After sequential phosphorylation of pRb by cyclin D/cdk4/6 and cyclin E/cdk2, E2F1 itself is also phosphorylated by cyclin D/cdk 4/6 complex at serine-332 and -337 positions, which increases the stability of E2F1 and prevents its binding to Rb irrespective of its phosphorylation status, thus ensuring the availability of free E2F1 at the G1/S transition point (5 , 33) . B) Dissociation of ppRb from E2F1 may facilitate binding of the factor acetyltransferase (FAT) complex CBP/p/CAF, which could bind to a region between amino acids 426–437 in the carboxyl terminus of E2F1 (61) and acetylate E2F1 lysine residues at positions 117, 120, and 125 (34) . Acetylation enhances DNA binding of the E2F1/DP1 dimer and further stabilizes E2F1. C) In late S phase, when cyclin A concentration builds up, it recruits cdk2 to E2F1 via an interaction with the cyclin A binding domain of E2F1. The cyclin A/cdk2 complex besides phosphorylating DP1 and causing its release, also phosphorylates E2F1 itself at serine-375 (35 36 37 38) . This phosphorylation of E2F1 reduces its DNA binding ability. D) In late S-G2 phase, down-regulation of E2F1 activity eventually occurs via degradation through proteasome pathway. The E2F1-induced expression of p14ARF (p19ARF; a mouse homologue) finally leads to binding of p14ARF to the carboxyl terminus of E2F1 (39) , which promotes the binding of p45skp2 ubiquitin protein ligase to the amino terminus of E2F1 (40) . After polyubiquitination, E2F1 is degraded via proteasome pathways (41 , 42) . Phosphorylation of serine-31 of E2F1 by ATM/ATR kinase could interfere with p45skp2 binding and reduce E2F1 degradation (43) .

The physical association of pRb with E2F1 protects the latter from degradation. At the same time, the deacetylase activity bound to pRb appears to maintain E2F1 in a deacetylated inactive form. Upon dissociation of ppRb, as shown in Fig. 2B , E2F1 is amenable to acetylation of lysine residues at 117, 120, and 125 positions just outside the DNA binding domain toward the amino terminus. Acetylation has been shown to enhance the stability as well as DNA binding activity of E2F1. Such acetylation appears to occur due to the factor acetyl transferase enzyme complex CBP/p/CAF that binds E2F1 at the carboxyl terminus (34) .

In mid-late S phase, the cyclin A-cdk2 complex has been shown to bind E2F1 at a specific domain that is amino-terminal to its DNA binding domain. After forming a stable complex with E2F1, the cyclin A-cdk2 complex phosphorylates serine-375 on E2F1 (Fig. 2C ) and reduces the DNA binding ability of E2F1-DP1 heterodimer (35 36 37) . Cyclin A bound cdk2 in a multiprotein complex with E2F1/DP1 heterodimer brings about phosphorylation of DP1, which could release E2F1 from DNA and DP1 (38) .

As depicted in Fig. 2D , an alternative reading frame protein, p14^ARF (p19^ARF, the mouse homologue), may eventually bind to the carboxyl terminus of E2F1 and flag it for ubiquitination, which proceeds through the binding of ubiquitin-protein ligase SCF^Skp2 to amino terminus of the protein (39 40 41) . After polyubiquitination, E2F1 is degraded via the proteasome pathway (42) . It has been shown that phosphorylation of serine-31 in the amino terminus region by Ataxia Telangiectasia mutant (ATM) kinase or ATM and Rad3-related kinase (ATR kinase) may interfere with the binding of ubiquitin-protein ligase and hence prevent degradation of E2F1 (43) . E2F1 stabilization and activity through phosphorylation by ATM/ATR kinases have been postulated to participate in a cellular response to DNA damage.

The subcellular localization of various E2F members seems to play a crucial role in their activity. As noted in Table 1 , only the activating E2Fs have a nuclear localization signal (NLS) in their protein, whereas the repressive E2Fs lacking indigenous NLS have to depend on either DP1 or pocket protein for their nuclear localization (for a review, see refs 2 , 3 ) Intriguingly, however, despite the presence of NLS in E2F1 protein, it is often found in cytoplasm as well (44 45 46 47) . Along with the increased E2F1 activity, its protein actively accumulates in the nucleus, indicating a probable involvement of other factors in its transport from cytoplasm (46 , 47) . The nuclear localization pattern reported for E2F1 resembling that of PML bodies may provide clues to the mechanism of its nuclear localization (48) . The prime modus operandi therefore to consider in this regard is a process of SUMOylation. In this reversible process of SUMOylation, a protein structurally similar to ubiquitin called SUMO is conjugated covalently to target cellular proteins, which increases their stability, brings about their localization in the nucleus, and enhances their activity (49) . Indeed, E2F1 protein shows a consensus amino acid sequence for SUMOylation: AK(x)_nD at the amino terminus lysine K 120 position. This highly speculative proposition of E2F1 interaction with SUMO contributing to its nuclear localization, however, awaits experimental evidence.

	CLINICAL IMPLICATIONS OF THE PROTEIN INTERACTIONS OF E2F1

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Transcription of many key players involved in E2F1 protein modification is directly under E2F1 regulation; in turn, all the components are maintained by feedback loops. Thus, an imbalance at any point in this complex network could affect E2F1 functioning and result in a pathologic situation. Besides its well-appreciated role in viral tumorigenesis, the functional derailment of E2F1 is suspected to contribute to the pathobiology of some cancers, myelodysplastic syndromes, defects in T cell development, immunodeficiency virus encephalitis, Down’s syndrome, postischemic brain infarct, etc. (44 45 46 , 50 51 52 53 54) . The molecular mechanism underlying the abnormal E2F1 activity may vary in individual disorder. Thus, a development of E2F1 inhibitors (Table 3 ), targeting its specific protein interactions, may have significant therapeutic implications in the future. Indeed, in myelodysplastic syndromes where E2F1 has been shown to be overexpressed and hyperactive, an addition of one such agent, Pentoxifylline, to the therapeutic regimen has been shown to provide definite clinical benefits (60) .

	ACKNOWLEDGMENTS

 
The authors wish to thank Drs. Marc Delcommenne and Guitta Maki for the review and valuable critique of our manuscript.

	REFERENCES

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