Cyclic AMP Response Element Binding (CREB) protein is a member of the CREB/ATF (Activating Transcription Factor) family of transcription factors playing an important role in the nuclear responses to a variety of external signals that lead to proliferation, differentiation, apoptosis and survival. Other authors’ evidences have highlighted a critical role of CREB in the regulation of normal haematopoiesis and leukemogenesis due to the interaction with target genes crucially involved in the cell cycle machinery. Recent findings of our research group have demonstrated that CREB and ATF-1 phosphorylation levels are related to a different sensitivity of T leukaemia cell clones to the cytotoxic action of TNF-related apoptosis inducing ligand (TRAIL) and that low dose radiation treatment of erythroleukaemia cells (K562) can trigger CREB activation and deliver a survival signal. Since one fundamental problem of most malignancies, including those of haematological origin, is the development of multiple mechanisms of resistance, which progressively reduce or suppress the therapeutic efficacy of anticancer treatment, the early identification of biological markers of responsiveness/unresponsiveness and the follow-up of individual response are highly desirable to adjust therapeutic treatments. In light of all these considerations and of the complex molecular interactions involving CREB/ATF family members, the present chapter is aimed at revising literature focusing, in particular, on the involvement of CREB/ATF family members in leukemogenesis and lymphomagenesis, in order to gain more insight into this matter that could result useful to the treatment of leukaemia and lymphoma diseases.
2. CREB family members
The CREB or CREB/ATF multigenic family is composed by several nuclear transcription factors. The prototype of this family is CREB, a 43 kDa – basic-region leucine zipper (bZIP) transcription factor that elicits responses to a variety of extracellular signals, including stress and growth factors, and that is involved in several cellular processes such as glucose homeostasis, proliferation, ageing and differentiation, survival and apoptosis, memory and learning . The CREB/ATF family of transcription factors includes three homologous genes: cAMP response element binding (
CREB/ATF proteins were initially identified for their binding to the cyclic AMP response element (CRE) in various gene promoters that contain the octanucleotide consensus sequence TGACGTCA . Over the years, cDNA clones encoding identical or homologous proteins have been isolated. Up to now, at least 20 different mammalian proteins with the prefix CREB or ATF have been characterized and grouped into subgroups on the basis of their amino acid similarity [5, 6]. CREB/ATF family members include CREB-1 (also known as CREB), CREB-2 (recently named ATF-4), CREB-3, CREB-5, CREM, ATF-1 (also known as TREB36), ATF-2 (also known as CRE-BP1), ATF-3, ATF-4 (previously named CREB-2), ATF-5 (also known as ATFX), ATF-6, ATF-7 and B-ATF subgroups [7, 8]. Proteins belonging to this class represent a large group of bZIP transcription factors containing highly divergent N-terminal domains, but sharing a C-terminal leucine zipper domain. The basic region in the bZIP domain is rich in basic amino acids and is responsible for specific DNA binding, while the leucine zipper region contains leucine residues and is responsible for dimerization of the proteins by resembling a zipper. Based on the sequence of each bZip domain, these proteins form homodimers or heterodimers both with other members of the family and with other bZIP containing proteins like the activator protein-1 (AP-1), C/EBP, Fos, Jun or Maf family proteins . That implies the expansion of the repertoire and different opportunities of target gene regulation that are further increased by the alternative splice products of
While both CREBs and ATF-1 are ubiquitously expressed, CREMs are mainly present in spermatids  and in the neuroendocrine system . Interestingly, a recently published paper on the effects of traumatic brain injury demonstrated the nuclear co-localization of CREM-1 and active caspase-3 in the ispilateral cortex of adult rats, suggesting a possible role for CREM-1 in neuronal apoptosis . In a recent report of our research group on Jurkat leukaemia cells , we observed a different cell compartmentalization of CREB protein in dependence of the TRAIL dose employed and induced cytotoxicity. Indeed, both under normal or low serum culture conditions an evident nuclear translocation of phospho-CREB was detected after 1 h treatment only with the lower dose of TRAIL (100 ng/mL) and prevented in the presence of PI3K/Akt and p38 mitogen-activated protein kinase (MAPK) specific inhibitors . In another model under investigation in our laboratories and represented by K562 erythroleukaemia cells induced to differentiation , the nuclear localization of the active form of CREB was clearly evident after only 1 h treatment with haemin. Interestingly, CREB positive nuclei resembled the features of apoptotic nuclei, suggesting that CREB phosphorylation is possibly required to determine the nuclear structural changes occurring during erythroblast maturation [21, 22]. Concerning other family members, it has been recently shown that ATF-2 is a nucleocytoplasmic shuttling protein and that its subcellular localization is regulated by AP-1 dimerization . ATF-3 is ubiquitously expressed and localized in the nucleus but maintained at low levels in the absence of cellular stresses. Instead, it is rapidly transcriptionally induced under different conditions, among which hypoxia, DNA damage (induced by UV radiation, ionizing radiation, etoposide), heat or cold shock, serum starvation or stimulation [13, 15]. ATF-4 is of particular interest since it has been demonstrated to translocate from the cytoplasmic membrane to the nucleus in neuronal cells upon γ aminobutyric acid (GABA) receptor activation, to be likely involved in neuronal plasticity by coupling receptor activity to gene expression . Finally, a number of immunofluorescent and cell fractionation experiments indicate that ATF-6 is linked to the endoplasmic reticulum (ER) chaperone Bip/Crp78 and localizes in the precursor form on the ER membrane . Upon ER stress induced by prolonged nutrient deprivation, it translocates to the Golgi where it is cleaved by resident proteases to liberate its active N-terminal domain. In this active form it translocates to the nucleus where it up-regulates a number of target genes involved in energy homeostasis .
3. CREB binding proteins
The human CREB-binding protein (CBP) and its paralogue, p300, are highly related proteins that are well conserved amongst mammals. Due to their high degree of sequence similarity, these two proteins are most often functionally interchangeable although they also possess unique functions [26, 27]. CBP was initially recognized as an interaction partner for CREB nuclear transcription factor , whereas p300 cDNA was cloned encoding the 300 kDa protein known to be associated with the adenoviral protein E1A . Though encoded by different genes, CBP/p300 share several conserved regions that constitute most of their known functional domains [for details see 27]. Both CBP and p300 have originally been described as transcriptional co-activators that bridge DNA-binding transcription factors to components of the basal transcriptional machinery, including the TATA-box-binding protein (TBP) , TFIIB  and, via RNA helicase A, also RNA polymerase II . Due to the huge size of over 2400 amino acids, CBP/p300 can also behave as a scaffold, bridging together a variety of cofactor proteins at the same time and leading to the assembly of multi-competent co-activator complexes [26, 27]. In addition, CBP/p300 interact with protein kinases such as the MAPKs and the cyclin E-Cdk2 complex, thus mediating the phosphorylation of CBP/p300-interacting transcription factors such as ER81 and E2F family members. Both CBP and p300 have been found originally to possess histone acetyltransferase (HAT) activity . This acetyltransferase function has profound consequences for nucleosomal structure and the activity of transcription factors, and thereby affects gene activity in multiple ways. In fact, it is well known that acetylation of multiple sites in the histone tails has been directly associated with transcriptional up-regulation, whereas de-acetylation correlates with transcriptional repression. Mechanistically, histone acetylation promotes the accessibility of DNA to transcription protein complexes, by facilitating the “unwiring” of the chromatin structure. During the last years, both CBP and p300 have been regarded as protein acetyltransferases rather than only HAT since they have shown the capacity to acetylate a number of non-histone nuclear proteins, including the tumour suppressor protein p53, dTCF, EKLF (erythroid Kruppel-like factor), GATA-1, NF-Y and other basal transcription factors [34, 35]. Thus, in light of the number of proteins interacting with CBP/p300, it is not surprising to find that many physiological processes, including cell growth, cell division, cell differentiation, cell transformation, embryogenesis and apoptosis, are dependent on CBP/p300 function [27, 28, 34]. Moreover, the importance of CBP/p300 is underscored by the fact that genetic alterations as well as their functional dysregulation are strongly linked to human diseases [36, 37].
Previous studies have shown that CBP and p300 play distinct roles in haematopoiesis and act non-redundantly in microenvironment-mediated haematopoietic regulation in spite of their high homology [38-40]. It has been widely documented that both proteins interact with crucial transcriptional regulators in virtually all haematopoietic lineages. Intriguingly, CBP/p300 can promote, on one hand, normal differentiation and cell cycle arrest (by cooperating with GATA-1) and, on the other hand, cell cycle progression and transformation by cooperating with c-Myb and PU.1, an Ets family transcription factor. It is conceivable that an overexpressed oncoprotein might compete with differentiation-inducing factors for CBP/p300 function. Furthermore, during normal development, CBP/p300 could differentially partition among transcriptional regulators with opposing functions, thus controlling the balance between proliferation and differentiation. As an example, the down-modulation of the proto-oncoproteins PU.1 and c-Myb during the erythroleukaemia MEL cell line maturation might increase availability of CBP/p300 for differentiation-associated factors such as GATA-1, NF-E2 and EKLF. Moreover, besides the involvement in erythroid cell lineage differentiation, CBP and, very likely, p300 target a broad range of myeloid and lymphoid expressed transcription factors [38-40].
Because of its central role in transcription, it is not surprising that aberrations in
4. CREB physiological roles and signalling pathways
CREB is a multi-functional transcriptional activator that is involved in many signalling pathways under normal and pathologic conditions. CREB mediates its transcriptional responses following phosphorylation at Ser133  and the consequent association with the 256 kDa co-activator CBP  or related family members like p300 . Both Ser133 phosphorylation and CBP association play an essential role for gene transactivation mediated by an octanucleotide CRE consensus sequence placed in the promoters of many cellular genes . In more detail, CREB transactivation domain, that is the site able to interact with other nuclear factors, contains a constitutive glutamine rich domain termed Q2 and an inducible domain, termed the kinase-inducible domain (KID), regulated by cellular kinases . The Q2 domain interacts with a TATA binding protein-associated factor and is constitutively active; instead, the KID region promotes isomerization by recruiting the co-activator factors CBP and p300 to the gene promoters and is active only when it is phosphorylated at Ser133 by a variety of cellular kinases. Recent studies using a genome-wide analysis showed that the number of putative target genes for CREB is about 5000, among which immediate-early genes, including
In the late 1980s, it was discovered that cAMP mediates the hormonal stimulation of several cellular processes by regulating the phosphorylation of critical proteins among which CREB transcription factor . Although it was initially identified as a target of the cAMP signalling pathway, studies on activation of immediate-early genes revealed that CREB is a substrate for kinases other than cAMP-dependent protein kinase A (PKA) and that various signalling routes converge on CREB and CREM, controlling their function by modulating their phosphorylation states [52, 53]. As above mentioned, almost all the signalling pathways that activate CREB lead to the phosphorylation of Ser133, which is required for CREB-induced gene transcription, but additional sites on CREB or on linked proteins can be phosphorylated exerting a modulation of CREB activity . For example, Ser133 phosphorylation primes CREB for phosphorylation by Glycogen synthase kinase 3 (GSK-3) at Ser129. However, unlike Ser133 phosphorylation, the physiologic consequences of Ser129 phosphorylation are not well defined, although evidence suggests that it is also linked to CREB activation . In different systems a number of different kinases have been shown to stimulate CREB phosphorylation and several CREB kinase candidates have been identified so far. PKA, which is activated by cAMP, is the major kinase that targets Ser133 in many processes [1, 3]. Other signalling molecules responsible for CREB Ser133 phosphorylation include mitogen- and stress-activated kinase 1 (MSK-1), extracellular signal-regulated kinase (ERK), calcium/calmodulin-dependent kinases (CaMKs), p90 ribosomal S6 kinase (RSK), MAPKs and Akt/protein kinase B (PKB) [1, 3, 7, 55, 56]. Both MAPK and Akt have been shown to enhance the survival of cultured cells by stimulating CREB-dependent target gene expression . CREB activity is also regulated by a family of cytoplasmic co-activators known as transducers of regulated CREB activity (TORCs) and including TORC1, TORC2 and TORC3. TORCs are activated by extracellular stimuli represented by nutrients (glucose) and hormones. Once activated, they translocate into the nucleus where they bind to the bZIP domain of CREB exerting its activation through a phospho-Ser133-independent mechanism. All TORCs are regarded as strong activators of CREB-dependent transcription .
In Fig. 1 the main factors and signalling molecules leading to CREB activation in haematopoietic cells are schematically represented.
5. CREB family members and leukemogenesis
Recent data suggest that CREB acts as a proto-oncogene in haematopoietic cells and contributes to the leukaemia phenotype [37, 38, 45, 46]. It has been shown anyway that CREB is able to promote tumour formation only when other oncogenes are also activated. In fact, its overexpression is not sufficient to induce acute leukaemia
Several CREB family members have been implicated in different malignant conditions. The first malignancy to be discovered was the clear cell sarcoma of the soft tissue (CSST). In this solid tumour, the cells are induced to proliferation by an Ewing’s Sarcoma (EWS)-ATF-1 fusion oncoprotein derived by a chromosomal translocation that fuses the DNA-binding and bZip domain of ATF-1 to the EWS gene. In haematological malignancies, CREB has been implicated in the pathogenesis of human T lymphotropic virus I (HTLV-I) related T-cell leukaemia  and also associated with the genesis of follicular lymphoma, where CREB binds to the CRE site in the promoter of translocated Bcl-2 . Other leukaemia-associated chromosomal translocations involving the CBP and p300 genes were also linked to haematological malignancies. These translocations generally result in fusion products that preserve most of the CBP and p300 molecules, suggesting that the disease mechanism does not simply involve loss of function of CBP, as is the case in Rubinstein-Taybi syndrome, but often implies an altered cofactor function (dominant positive or dominant negative) through fusion to another molecule. The most frequent chromosomal translocations targeting
5.1. Acute myeloid leukaemia
Acute leukaemia derives from the clonal expansion of haematopoietic stem/progenitor cells that have lost their ability to undergo terminal differentiation. Since transcription factors control HSC production and differentiation, it is conceivable that disorders of the haematopoietic system often involve alterations of the regulatory network of transcription factors. In haematological malignancies transcription factors can be overexpressed, involved in chromosomal translocations or become targets of somatic mutations that disrupt their normal function [37, 60-63]. Previous studies have demonstrated that
Clinical and experimental findings underline that AML is induced by numerous functionally cooperating genetic alterations, including chromosomal translocations that lead to the expression of fusion proteins often behaving as aberrant transcription factors. Several AML-associated lesions target chromatin regulators like histone methyltransferases or histone acetyltransferases, including MLL1 or CBP/p300 . As already mentioned, CBP is an adapter protein that is involved in regulating transcription and histone acetylation, through which it is thought to contribute to an increased level of gene expression. The
Myelodysplastic syndromes (MDS) include a heterogeneous group of clonal haematopoietic stem cell malignancies with significant morbidity and high mortality. The incidence of MDS increases markedly with age and the disease is most prevalent in individuals who are white and male. Because of an ageing population and an improving awareness of the disease, the documented disease burden is expected to worsen in the near future. Due to the poor survival of individuals with MDS, it is important to identify prognostic factors to better risk-stratify patients for more effective treatments . Genomic instability is associated with progression of the disease so that a part of patients develops AML. It has been reported that an increased incidence of haematological malignancies occurs in
5.2. Acute lymphoblastic leukaemia
Acute lymphoblastic leukaemia (ALL) is a heterogeneous disease characterized by the predominance of immature haematopoietic cells, in which malignant cells express phenotypes of either T-cell or B-cell lineages . ALLs account for the 25-30% of all cancer diagnoses in children. CREB involvement in the molecular events related to
In our laboratory we have investigated the role of PI3K/Akt pathway and CREB family members in a number of lymphoid and erythroleukaemia cell lines treated with chemical and physical agents inducing cell death by apoptosis or necrosis [20, 21, 47, 77-80]. We first detected with Western Blotting a high constitutive level of CREB phosphorylation at Ser133 in Jurkat T cells under normal serum culture conditions . Under low serum culture conditions, an early (within 1 h) and transient increase in CREB phosphorylation was observed in response to TRAIL treatment and reduced upon pre-treatment with LY294002 or SB253580, demonstrating the PI3K/Akt- and p38 MAPK-dependency of this effect. Interestingly, both phospho-CREB and phospho-ATF-1 were down-regulated in response to TRAIL treatment of normal primary cells derived from haematopoietic precursors (HUVEC, HEMA), whereas both of them were up-regulated in the neoplastic counterparts (K562 cell line) [20, 21]. The PI3K/Akt pathway dependency of CREB/ATF-1 phosphorylation induced by TRAIL treatment was demonstrated both in primary cells and in leukaemia cell lines of different origin and TRAIL sensitivity, showing that the observed phenomenon is a general feature of TRAIL action in leukaemia [77, 80]. In addition, the observation of CREB cleavage products upon TRAIL/LY294002 combined treatment of sensitive leukaemia cells was consistent with previous reports on other neoplastic cell lines  and compatible with the TRAIL-mediated activation of the caspase cascade and cleavage of anti-apoptotic molecules. The parallel analysis with immune fluorescence demonstrated the nuclear translocation of the phosphorylated form of CREB upon treatment with 100 ng/mL TRAIL, whereas the immune labelling was mainly detectable in the cytoplasm compartment upon the higher more cytotoxic dose (1000 ng/mL) as shown in Fig. 2. A further enhancement of apoptotic cell death was obtained with the use of CREB1 siRNA technology leading us to hypothesize that CREB activation can have an important role in the complex crosstalk among pro- and anti-apoptotic pathways in Jurkat T cells [20, 80].
5.3. Chronic myelogenous leukaemia
Chronic myelogenous leukaemia (CML) is characterized in the 85-90% of the cases by the presence of the Philadelphia (Ph) chromosome and the
5.4. Chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia (CLL) originates from the abnormal accumulation of antigen-stimulated B cells that escape normal cell death mechanisms and/or undergo increased proliferation . CLL is the most prevalent adult leukaemia in the Western world, yet no curative treatment exists. Many studies have explored the use of family-specific cyclic nucleotide phosphodiesterase (PDE) inhibitors in light of the potent effects of cAMP signalling on immune system function [88, 89]. Among the 11 currently known families of cyclic nucleotide PDEs, all but three are capable of catabolizing cAMP and at least 5 PDE families (PDE1-4, PDE7 and PDE8) are expressed in lymphoid cells and regulated by either mitogens or agents that induce cAMP-mediated signalling. Previous work has established that inhibition of PDE4 is sufficient to selectively induce apoptosis in CLL cells by increasing the concentration of cAMP . In a recent paper Meyers et al.  examined how CLL cells differ from normal haematopoietic cells with regard to their sensitivity to PDE4 inhibitor-mediated cAMP accumulation, CREB phosphorylation and gene expression. Interestingly, it was discovered that upon exposure to rolipram, a prototypical PDE4 inhibitor, cAMP intracellular levels rapidly rose in both CLL and normal B cells, whereas no such increase was detected in T cells. Likewise, ATF-1/CREB Ser63/133 phosphorylation was induced by rolipram in nearly all CLL and B cells, whereas normal T cells displayed a lower response. Based on these findings and on previous observations of a reduced basal cAMP signalling in CLL cells, the authors suggested the involvement of specific PDE or splice isoforms in the reduced basal apoptotic index of CLL cells . Looking for etiological agents, other authors have identified a stromal cell–derived factor-1 (SDF-1)-dependent mechanism as a microenvironmental regulatory mechanism of CLL cell survival . It is known that SDF-1 is a chemokine that plays an important role in B-cell development. In fact, high levels of SDF-1 are produced by stromal cells within the marrow to retain B-cell precursors in close contact with them, within the supportive haematopoietic microenvironment , and to prevent their premature release into the circulation. Upon
5.5. Human T Lymphotropic Virus 1 (HTLV-1) related T cell leukaemia
Human T-cell leukaemia virus type-I (HTLV-1) is the first discovered human retrovirus . It has been recognized as the etiological agent of an aggressive malignancy known as adult T-cell leukaemia (ATL) as well as of the neurological syndrome TSP/HAM and of other clinical disorders.
Lymphomas are haematological malignancies of the lymphoid system. Deregulated gene expression is a hallmark of cancer and is well documented in B-cell lymphomas . B cells are particularly susceptible to malignant transformation since the mechanisms involved in antibody diversification can cause chromosomal translocations and oncogenic mutations. B-cell lymphomas include Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (B-NHL). B-NHL consists of a heterogeneous group of diseases whose pathogenesis is associated with multiple genetic lesions affecting oncogenes and tumour-suppressor genes and whose treatment is related to the different grade of malignancy. The most common type of B-NHL is represented by the diffuse large B-cell lymphoma (DLBCL), which generally arises as a clinical evolution of the follicular lymphoma (FL). A number of papers have demonstrated the involvement of CREB family members in the pathogenesis of lymphoma. It has been previously found that CREB acts as a positive regulator of the translocated
5.7. Multiple myeloma
Multiple myeloma (MM), also known as plasma cell myeloma or Kahler's disease, is a B-cell malignancy characterized by the accumulation in the bone marrow of plasma cells with a low proliferation index and an extended life span. Most cases of myeloma also feature the production of a paraprotein, an abnormal antibody that can cause kidney problems. MM cell lines as well as
6. Concluding remarks
CREB/ATF family is a growing family of transcription factors involved in a number of physiological and pathological processes. Day by day, new family members are being identified for their primary role in normal or aberrant haematopoiesis and proposed as therapeutic targets of anticancer drugs . In fact, by regulating gene expression, transcription factors are often the final mediators of such central processes as proliferation, survival, self-renewal and invasion. Based on these effects, it is conceivable that inhibition of transcription factors can revert the malignant behaviour of many tumour types and can potentially achieve a very high therapeutic index . Actually, in light of its important role in the pathogenesis of leukaemia, CREB has been indicated as a potential prognostic marker of disease progression in AML and a molecular target for future treatment of leukaemia. In addition, CREB has also been implicated in many solid tumours including hepatocellular carcinoma, osteosarcoma, lung adenocarcinoma, melanoma and lymphoma . Indeed, since
AcknowledgmentsThis book chapter was supported by funds of the Italian Ministry of University and Research (MIUR) granted in 2011 to Prof. Roberta Di Pietro.
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