Transcriptional Regulators and Myelopoiesis - Wiley Online Library

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Concise Review Transcriptional Regulators and Myelopoiesis: The Role of Serum Response Factor and CREB as Targets of Cytokine Signaling PATRICIA MORA-GARCIA,a JERRY CHENG,a HEATHER N. CRANS-VARGAS,a,b ATHENA COUNTOURIOTIS,a DEEPA SHANKAR,a KATHLEEN M. SAKAMOTOa,b a

Department of Pediatrics, Division of Hematology-Oncology, Mattel Children’s Hospital, Gwynne Hazen Cherry Memorial Laboratories, Jonsson Comprehensive Cancer Center, and bDepartment of Experimental Pathology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA Key Words. Hematopoiesis · SRF-CREB · Leukemia · Signal transduction · Transcription factors

A BSTRACT Hematopoiesis is a complex process in which mature myeloid and lymphoid cells are produced from a small population of pluripotent stem cells within the bone marrow. Blood cell formation occurs, in part, by progenitor cell exposure to humoral growth regulators, known as hematopoietic cytokines, as well as by the regulated expression of genes by

transcription factors. In this paper, we review two important nuclear proteins, the serum response factor and the cyclic adenosine monophosphate response element-binding protein, as downstream targets of mitogens, with a specific focus on hematopoietic cytokine signaling and the role these proteins play in gene regulation. Stem Cells 2003;21:123-130

CYTOKINES AND THEIR RECEPTORS Cytokines are soluble proteins that enable cells to communicate with their extracellular environment through their interaction with specific glycoprotein receptors present on the cell surface. Most cytokines are pleiotropic, having multiple functions, and demonstrate redundancy in their biological actions due to shared subunits among receptors [1, 2]. Cytokine receptors are categorized based on their structural homology and include receptor tyrosine kinases, antigen receptors, the tumor necrosis factor (TNF) receptor superfamily, protein serine/threonine kinase receptors, and the cytokine receptor superfamily [3, 4]. Activated cytokine receptors mediate diverse biological responses, such as adaptive inflammatory host defenses, cell growth and differentiation,

cell survival and cell death, angiogenesis, embryonic development, and repair processes [5-10]. Cytokine receptors mediate these responses through the activation of intracellular signaling cascades that ultimately regulate gene expression through nuclear transcription factors. The class I cytokine receptor superfamily represents one of four cytokine receptor subgroups and includes transmembrane protein receptors for both hematopoietic and nonhematopoietic ligands, such as hormones, interleukins, and colony-stimulating factors [6]. This receptor superfamily shares a conserved cysteine and WSXWS motif within the extracellular domain in addition to a single conserved membrane proximal domain in the intracellular region [11-13]. The cytoplasmic domains of these receptors are devoid of

Correspondence: Kathleen M. Sakamoto, M.D., Division of Hematology-Oncology, Department of Pediatrics, Mattel Children’s Hospital, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, California 900951752, USA. Telephone: 310-794-7007; Fax: 310-206-8089; e-mail: [email protected] Received September 13, 2002; accepted for publication October 8, 2002. ©AlphaMed Press 1066-5099/2003/$5.00/0

STEM CELLS 2003;21:123-130

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any intrinsic kinase activity and require the association of tyrosine kinases to mediate receptor-activated signaling cascades and gene transcription. Activation of the class I cytokine receptors by their cognate ligands results in the formation of homodimeric, heterodimeric, or oligomeric receptor structures consisting of one or more types of receptor subunits [3, 6, 14, 15]. Furthermore, they are grouped into subfamilies according to their shared subunit composition. For example, the GM-CSF, interleukin-3 (IL-3), and IL-5 receptors are composed of a ligand-binding α subunit and a common β subunit (βc). The α subunit is cytokine specific and binds the ligand with low affinity, while the βc subunit associates with both the ligand and the α subunit through high-affinity interactions. The βc subunit is responsible for the overlapping biological activities of the GM-CSF, IL-3, and IL-5 receptors. Ligand binding produces dimerization of the α and β subunits and subsequent heterodimerization. In contrast, receptors for erythropoietin (EPO), G-CSF, thrombopoietin (TPO), growth hormone, and prolactin are composed of homodimeric subunits [3, 14-16]. SRF AND CREB ARE TARGETS OF CYTOKINE RECEPTOR SIGNALING Two important gene regulators activated by cytokine receptors in hematopoiesis are cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and serum response factor (SRF). These transcription factors have been shown to regulate the expression of immediate early genes, such as c-fos and egr-1 [17-23], which are induced in response to growth factor stimulation [24-27]. Since CREB and SRF are both transcription factors activated by distinct signaling cascades, they regulate cell proliferation, differentiation, and survival through the induction of key target genes. Furthermore, CREB and SRF associate with coregulators to control gene expression in a cell-type-specific manner. SRF SRF is a ubiquitously expressed protein (67 kDa) belonging to the MADs box family of nuclear transcription factors [28-30]. The MADS box is a highly conserved motif found in a family of transcription factors. The conserved domain was recognized after the first four members, including MCM1, AGAMOUS, DEFICIENS, and SRF. Most MADS domain proteins play important roles in development [29]. SRF mediates biological processes, including hematopoiesis, myogenesis, and embryonic development. SRF is also activated in response to various stimuli, including serum, growth factors, and intracellular calcium-regulating agents [21, 23, 28, 3133]. There is also recent evidence that SRF may play a role in metastatic tumor progression [34].

SRF and CREB in Myelopoiesis Structurally, SRF is composed of an aminoterminal DNAbinding domain, containing a conserved 56-amino-acid MADs box, a central dimerization domain, and a C-terminal transcriptional activation domain [21, 23]. The SRF is phosphorylated at serine 103, which is located N-terminal to the MADS motif and regulates SRF binding to DNA [35]. Phosphorylation at serine 103 occurs through activation of kinases, including the serine threonine kinase pp90RSK [36], the stress-regulated mitogen-activated protein kinase-activated protein kinase 2 [37], and the calcium-regulated CaM kinases II and IV [28, 38]. A SRF homodimer participates in coordinating mitogeninducible and muscle-specific gene transcription through its direct binding to the CArG box motif (CC[A/T]6GG) of the serum response element (SRE) [21, 22]. As it binds DNA, SRF regulates gene transcription either directly or through association with other cofactors [21, 22, 39-41]. SRF has been demonstrated to interact with other transcription factors, such as ternary complex factors (TCFs) and CCAAT/enhancer-binding protein β (C/EBPβ). Coregulated SRE-dependent transcription in response to mitogens leads to induction of the immediate early genes, c-fos and egr-1. The TCFs, Elk-1 and Sap1, belong to the ETS protein family of transcription factors and bind to adjacent SRE sites to form a ternary complex with SRF [42-44]. Elk-1 and Sap1 directly contact SRF through a B-box motif, which is C-terminal to their ETS DNA-binding domains [45, 46]. In studies of Elk1/SRF interactions with the SRE DNA sequence, Elk-1 is recruited to an ETS binding site after an SRF homodimer binds to an adjacent CArG motif in the c-fos promoter. Transcriptional activation of c-fos by the ternary complex is dependent on TCF phosphorylation by the Ras/mitogen-activated protein kinase (MAPK) pathway [47-51]. Furthermore, transcriptional activation of the c-fos SRE is potentiated by coactivator proteins of the CREB binding protein (CBP)/p300 family [52]. Recent work by Nissen et al. suggests a model in which CBP forms a higher order complex with the TCF through its direct interaction with ELK-1, facilitating the rapid transcriptional activation of c-fos upon phosphorylation of the TCF proteins [52]. The C/EBPβ also associates with SRF and coordinates SRE-1 expression through extracellular signalregulated kinase- and pp90RSK2-signaling pathways [53]. SRF regulation of gene transcription has been shown to occur through a manner independent of Ras and TCF proteins. Serum and lysophosphatidic acid directly activate SRF through certain members of the Rho GTPase family (RhoA, Rac1, and CDC42) [54-56]. This pathway requires that SRF binds DNA through its DNA-binding domain and then associates with an unknown accessory factor of SRF [54, 57]. The tumor-promoting agent, TPA, also activates SRF through a phosphoinositide-3 kinase (PI3K)-dependentand TCF-independent pathway [58].

Mora-Garcia, Cheng, Crans-Vargas et al. SRF AND HEMATOPOIESIS SRF is widely expressed in hematopoietic cell lines of both the myeloid and lymphoid cell origins [59, 60]. SRF is activated in response to various cytokines, including G-CSF, GM-CSF, IL-3, IL-2, IL-5, and EPO, in addition to T-cellreceptor (TCR) activation [17-20, 61]. SRF participates in regulating SRE-dependent c-fos expression and proliferation upon T-cell-receptor engagement by overexpressing the guanine nucleotide exchange factor Vav1. Vav1 induces SRE-1-dependent transcription in a Rac1/Cdc42Pak1-MEK1- dependent pathway, resulting in SRF phosphorylation at serine 103 leading to increased SRF binding to the SRE [20]. The SRE has been demonstrated to play an important role in cytokine-regulated gene expression. GM-CSF induces expression of egr-1 in the human myeloid leukemic cell line TF-1 through the SRE and an adjacent cAMP response element (CRE) between nucleotides (nts) -116 and -56 of the promoter relative to the transcription start site [17]. Both the SRE and the CRE are required for maximal transcriptional activation of egr-1 in response to GM-CSF, and thus, may work independently of each other [62]. Similarly, a GMCSF/IL-3 fusion protein, PIXY321, requires the same SRE and CRE for maximal induction of egr-1 [63]. In the mouse pro-B-cell line BA/F3, both GM-CSF and IL-3 control egr-1 and c-fos expression through SREs [18]. Two egr-1 promoter regions, the SRE-1/CRE between nts -116 and -56 and tandem repeats of SREs between nts -235 and -480 are both responsive to GM-CSF and IL-3, while an overlapping SRE and activator protein-1 sequence appears essential for c-fos activation by GM-CSF [18]. In other studies, the SRE and a STAT-binding site (SIE) were found to be required for GMCSF-regulated c-fos expression in TF-1 cells, the SIE being bound by STAT-3 in a GM-CSF-inducible manner [64]. Mutational analysis of the βc subunit of the GM-CSF receptor demonstrated that similar regions are required for transcriptional activation of both the egr-1 and c-fos genes. Furthermore, it appears that GM-CSF and IL-3 mediate egr1 and c-fos expression and activation of SRE-binding proteins through Ras [18]. Therefore, the receptors for GM-CSF and IL-3 are able to regulate egr-1 or c-fos expression through converging pathways that target the SRE due to similarities in their receptor structure and cross-talk in their signaling pathways. Further support for this is the ability of IL-2 to activate c-fos transcription through activation of SREbinding proteins in BA/F3 cells expressing the IL-2 β receptor. The SRE-binding proteins are similarly activated by IL-3 and EPO, whose receptors share regions of homology with IL-2 in their cytoplasmic domains [61]. SRF also plays a role in G-CSF-induced egr-1 expression in the murine myeloid leukemic cell line, NFS60 [19]. We

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demonstrated that SRF constitutively binds the CArG box of an SRE motif that is flanked by two ETS-protein-binding sites (known as SRE-1) and that lies between nts -418 and -391 of the egr-1 promoter. A single copy of SRE-1 is sufficient to induce transcriptional activation of a reporter gene in response to G-CSF. Furthermore, mutational analysis of the SRE-1 demonstrated that the SRE and ETS binding sites are both required for maximal induction of SRE-1 in response to GCSF. SRF binds the SRE-1 in the presence and absence of GCSF stimulation, as demonstrated by electromobility shift assays using NFS60 nuclear extracts. The oncoprotein Fli-1 binds the 5′ Ets-binding site of SRE-1, predominantly in GCSF-stimulated cells (unpublished observations) and independently of SRF. This suggests that SRE-1 is coregulated by SRF and the ETS protein(s) that bind the SRE-1 in response to G-CSF-receptor activation. Furthermore, G-CSF induces activation by SRE-binding proteins and SRE-1-dependent transcription through a MAPK and PI3K-dependent pathway (Fig. 1) [65]. CREB CREB is a member of the CREB/activating transcription factor 1/CRE modulator (CREM) family of transcription factors. The CREB protein contains a domain responsible for DNA binding and dimerization, a basic leucine zipper (bZIP), a kinase-inducible domain with several phosphorylation sites, and two glutamine-rich transactivation domains. CREB mediates cAMP, growth-factor-

Figure 1. Hypothesized model of G-CSF-induced egr-1 expression in myeloid leukemia cells. G-CSF activates egr-1 gene transcription in NFS60 cells through the interaction of SRE-binding proteins, SRF and Fli-1, with the SRE-1 sequence. Our results suggest that SRE-1 mediates egr-1 induction in response to G-CSF through a MEK/ERK1 and PI3K-dependent pathway.

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dependent and calcium-dependent gene expression through the CRE. The cAMP pathway transmits signals propagated by hormones, growth factors, and neurotransmitters in a cell-type-specific manner. CREB functions in growth-factor-dependent cell survival, glucose homeostasis, and in learning and memory [66]. The biological effects of CREB are mediated by phosphorylation at serine 133, which results in cellular gene expression critical for genetic programs regulating proliferation, differentiation, and survival. Additional promoterbound factors are required for target gene activation in response to certain mitogens or stress signals [67]. Phosphorylation of CREB at serine 133 appears to enhance the transactivation potential of CREB by promoting the recruitment of the coactivators CREB-binding protein (CBP) and p300 to the transcriptional machinery [67, 68]. Activation of CREB may, therefore, promote the transcription of key target genes that regulate specific programs of hematopoietic cell proliferation and differentiation. The activation of CREB is required for the induction of specific genes by growth factors. For example, the immediate early gene, c-fos, is rapidly and transiently induced by nerve growth factor, and egr-1 is upregulated in cells stimulated with GM-CSF [62, 69, 70]. egr-1 is critical for transcription of myeloid-specific proteins that function as determinants of myeloid cell differentiation [62, 71]. CREB binds to the CRE, which consists of an 8-nucleotide sequence (TGACGTCA) and is usually located 100 nucleotides upstream from the TATA box in promoters of certain genes [72]. CRE-binding proteins have been found to play an important role in the physiology of the pituitary gland, in regulating spermatogenesis, in the response to circadian rhythms, and in the molecular basis of memory. Their role in hematopoiesis is currently being investigated. Defects in CREB signaling have been associated with two disease conditions in humans. Cognitive defects in neurofibromatosis type 1 and mental retardation have recently been linked to disruptions of ras and its downstream targets, ERK and CREB [73]. CREB has also been linked to the disease, Coffin-Lowry Syndrome [74]. CREB KINASES Several kinases upstream of CREB have been identified. Phosphorylation of CREB by MAP kinase and Akt/protein kinase B has been shown to be important for cellular survival in cultured cells [75]. We and others have demonstrated that pp90RSK activates CREB [17, 70]. The mitogen- and stress-induced phosphorylation of CREB at serine 133 has been linked to the transcription of several immediate early genes, such as c-fos, junB, and egr-1.

SRF and CREB in Myelopoiesis In mice with a double knockout of both mitogen- and stress-activated protein kinase 1 (MSK1) and MSK2, the mitogen- and stress-induced phosphorylation of CREB in fibroblasts is inhibited [76]. Recently, a new role for CREB was identified in a human osteosarcoma cell line, L929, affected by mitochondrial dysfunction. In normal L929 cells, CaMKIV blocks activation of CREB [77]. However, in L929 cells that have mitochondrial defects, CaMKIV activity is impaired. Thus, CREB is constitutively phosphorylated, resulting in decreased cell proliferation. The mechanism of abnormal CREB activation is thought to be due to high intracellular calcium concentrations that disrupt the interaction of CaMKIV with protein phosphatase 2A resulting in persistently activated CaMKIV. CREB AND HEMATOPOIESIS CREB is a key mediator of critical target genes that control myeloid cell proliferation and differentiation. CREB transcriptionally regulates expression of the immediate early gene-1, egr-1, through GM-CSF-activated signaling pathways in the human erythroid cell line, TF-1 [62]. We previously demonstrated that GM-CSF induces CREB phosphorylation at serine 133 through a protein kinase A (PKA)-independent pathway [78]. Further investigation led to the discovery that CREB is phosphorylated at serine 133 by the serine threonine kinase, pp90RSK (ribosomal S6 kinase) [17]. pp90RSK is activated in response to GM-CSF in the human myeloid leukemic cell line TF-1 through an MEK-dependent signaling pathway (Fig. 2) [17]. Work by others also demonstrated that stimulation of TF-1 cells with IL-3 and GM-CSF resulted in CREB activation through a protein kinase C (PKC)-ε-dependent pathway. In contrast, IL-4 stimulation of TF-1 cells did not result in CREB phosphorylation at serine 133 [79]. These results suggest that there is specificity among nuclear proteins that are activated downstream of signaling pathways in response to distinct cytokine receptors. CREB also appears to play an important regulatory role in megakaryocyte differentiation. Agonists of megakaryocyte differentiation, including TPO, forskolin (FK), and phorbol myristate acetate (PMA), were added to the culture media of biphenotypic (erythroid/megakaryocytic) human erythroleukemia (HEL) cells, and levels of phosphorylated CREB were measured. High levels of CREB were noted to be phosphorylated at serine 133 (CREB-PSer133) in HEL cells and CD34+ cells acquired from normal donors in the presence of the cytokines TPO, FK, and PMA. Furthermore, TPO-induced activation of CREB in HEL cells through mechanisms that were not PKC or PKA dependent, but were MAPK dependent [80]. Recently, it has been suggested

Mora-Garcia, Cheng, Crans-Vargas et al.

Figure 2. Model of GM-CSF-induced egr-1 transactivation in myeloid leukemia cells. GM-CSF regulates egr-1 transcription in TF-1 cells through activation of CREB, which constitutively binds CRE. In response to GM-CSF, CREB is phosphorylated at serine 133 by the serine/threonine kinase, pp90RSK, through a MEK/ERK-dependent pathway as well as the PKCdependent pathway. Abbreviations: PI-PLC = phosphatidylinositol-specific phospholipase C; DAG = 1,2-diacylglycerol.

that TPO potentiates IL-3-dependent proliferation of hematopoietic progenitors and thereby upregulates PKC-ε [81]. THE ROLE OF CREB IN MYELOID AND LYMPHOID MALIGNANCIES The observation that CREB regulates hematopoietic cell proliferation in response to growth-promoting agents and cytokines suggests that CREB plays a role in normal and neoplastic hematopoiesis. In fact, CREB has been implicated in the pathogenesis of human T lymphotropic virus I (HTLV-I)related T-cell leukemias [82]. The transcriptional activator, Tax, enhances the CRE-binding activity of CREB. Tax associates with CREB as a stable complex, resulting in

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increased promoter activity of viral and cellular genes. CREB has also been implicated in the pathogenesis of lymphomas. CREB binds the CRE site in the promoter of translocated bcl2 in follicular lymphoma with the t(14;18) translocation but not normal alleles in both follicular and transformed lymphomas [83, 84]. CREB was found to recognize the CRE site in vitro and transcriptionally activate bcl-2 promoter expression by IgH enhancers in transient transfection experiments. Thus, CREB acts as a positive regulator of the translocated bcl-2 allele in follicular lymphomas with the t(14;18) translocation. In normal B cells, CREB is phosphorylated in response to signaling by the B-cell receptors, resulting in proliferation [85]. Finally, members of the CREB family have emerged as important cofactors in the hematopoietic system. Chromosomal translocations involving the CBP and a related family member, p300 genes, for example, have been associated with specific subtypes of myeloid leukemia, underscoring the importance of these genes in the regulation of hematopoietic cell differentiation and proliferation [86, 87]. Interestingly, these translocations resulted in leukemias of the myeloid/monocytic lineage [88]. Taken together, members of the CREB family of proteins regulate important pathways in myelopoiesis. To determine the possible role of CREB in leukemogenesis, we analyzed primary bone marrow cells for CREB expression from patients with acute leukemia at diagnosis, remission, and relapse. We observed that the CREB protein was expressed at a higher detectable level in bone marrow from patients with acute myeloid and lymphoid leukemia than in bone marrow from patients in remission or individuals without leukemia [89]. Interestingly, CREB expression was observed in bone marrow from leukemia patients at diagnosis and relapse, but not remission. Immunohistochemistry further demonstrated that the blast cells from patients with acute lymphoblastic leukemia, but not normal lymphocytes, expressed higher detectable levels of CREB. Preliminary studies in a small cohort of patients with acute myeloid leukemia suggest that the presence of elevated levels of CREB is associated with an increased risk of relapse and decreased event-free survival (unpublished observations). Thus, CREB may be a molecular marker of the leukemic clone that reflects uncontrolled proliferation or increased survival of hematopoietic progenitor cells in the bone marrow. Preliminary results from our laboratory suggest that CREB overexpression increases cell survival in myeloid leukemia cell lines (D. Shankar and K.M. Sakamoto, unpublished data). Future work will determine the mechanism of CREB overexpression in leukemia cells and the significance of increased CREB expression in the prognosis and treatment of patients with acute leukemia.

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SUMMARY In this review, we discussed two important nuclear proteins, SRF and CREB, as downstream targets of hematopoietic cytokine signaling. Although both SRF and CREB are ubiquitously present in cells, recent data suggest that they are regulated through various kinases and cofactors that yield tissue-specific changes in gene expression. We, as well as others, have described a possible link between ubiquitously expressed transcription factors, such as CREB and myc, and hematopoietic malignancies. Future studies will elucidate the precise role that these proteins play in oncogenesis.

SRF and CREB in Myelopoiesis ACKNOWLEDGMENTS Research support was provided by NIH (NCI) CA68221, Leukemia and Lymphoma Society of America, and American Cancer Society RSG-99-081-04-LIB (K.M.S.). H.N. Crans-Vargas is supported by an NIH Clinical and Fundamental Immunology Training Grant AI07126-25. A. Countouriotis is a recipient of the Resident Research Grant from the American Academy of Pediatrics. Deepa Shankar is supported by the Hamburger Endowment, UCLA Jonsson Comprehensive Cancer Center.

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