p38 mitogen-activated protein kinase and hematologic malignancies.
The p38 MAPK pathway was originally described as a mammalian homolog to a yeast osmolarity sensing pathway. (3) The most well-known role of the p38 pathway is as a transducer of responses to environment stress (such as hyperosmolarity, ultraviolet irradiation, and heat shock) and as receptors binding by proinflammatory molecules (eg, endotoxin, tumor necrosis factor a [TNF-[alpha]], and interleukin [IL] 1). Downstream substrates of p38 MAPK involve a variety of proteins, including kinases, cell cycle and apoptosis regulators, and transcription factors. Additionally, p38 MAPKs also perform posttranscriptional regulation of cytokines such as TNF-[alpha] and IL-1p. (4-8) Thus, p38 MAPK signaling has been implicated in responses ranging from apoptosis to cell cycle, induction of expression of cytokine genes, and differentiation. (9-15) This plethora of activators conveys the complexity of the p38 pathway. This complexity is further complicated by the observation that the specific downstream effects of p38 MAPK activation depends not only on stimuli but also on cell types and perhaps also on various p38 MAPK isoforms involved. (16-18) This review focuses on the recent advancement of p38 MAPK isoforms as well as the role of p38 MAPK in hematologic malignancies.
REGULATION AND ACTIVATION OF p38 MAPK SIGNALING CASCADES
To activate p38 MAPK by various stimuli, there is a requirement for dual phosphorylation on threonine and tyrosine residues present in specific motifs (threonine-glycine-tyrosine) located in the activation loop. (3,19,20) This phosphorylation is regulated by upstream dual-specificity kinases (MAPK kinases, [MAPKKs]) including MKK3, MKK4, and MKK6, which are capable of phosphorylating MAPKs on both serine and threonine as well as on tyrosine residues. MAPKKs exhibit relative specificity for the substrate MAPK proteins that they phosphorylate. The activation of MAPKKs is regulated by other upstream serine-threonine kinases, called MAPKK kinases, which phosphorylate the MAPKKs on specific serine residues. MAPKK kinases that regulate activation of p38 MAPK include kinases (Mlk1, Mlk2, Mlk3, Dlk, and Lzk), Mekk kinases (Mekk1, Mekk2, Mekk3, and Mekk4), Tak1, Ask1, Ask2, and Tpl- (2.20-26) Activation of the MAPKK kinases or MAPKKs occurs downstream from small G proteins whose function is regulated by the guanine exchange factor proteins. The small G proteins that regulate activation of p38 MAPK include members of the Rho family of proteins (Rac1, Cdc42, RhoA, and RhoB). (11,17,27) Thus, initial activation of guanine exchange factors leads to activation of GTPases and downstream initiation of distinct kinase cascades that regulate the activation of p38 MAPK.
[FIGURE 1 OMITTED]
p38 MAPK ISOFORMS
To date, 4 isoforms of the p38 family have been identified: p38[alpha], p38[beta], p38[gamma] (extracellular signal-regulated kinases 6, SAPK3), and p38[delta] (SAPK4). These isoforms are encoded by the genes located at 6p21.3-p21.2 ([alpha]), 22q13.33 ([beta] and [gamma]), and 6p21.31 ([delta]), respectively (28-30) (http:// www.ncbi.nlm.nih.gov/projects/mapview; accessed December 28, 2008). All p38 isoforms are characterized by a threonine-glycine-tyrosine dual-phosphorylation motif. (20,31) Sequence comparisons have revealed that each p38 isoform shares ~60% identity within the p38 group but only 40% to 45% to the other 3 MAPK family members. Of these, p38[alpha] and p38p are ubiquitously expressed in most tissues, whereas p38[gamma] and p38[delta] are differentially expressed depending on tissue type. (19,20) The p38[gamma] gene is highly expressed in muscle and the p38[delta] gene is upregulated in the lung, pancreas, testes, small intestine, kidney, and endocrine glands.
Expression of these isoforms in hematopoietic cells is not well documented. However, differentiation of stage-specific expression of p38 MAPK isoforms has been shown in primary human erythroid cells. In the differentiation of erythroid progenitors, p38[alpha] and p38[gamma] isoforms are continuously expressed throughout differentiation from lineage uncommitted [CD34.sup.+] early hematopoietic cells to terminally differentiated enucleating erythroblasts, which suggests distinct functions for these 2 isoforms in hematopoiesis. (25) On the other hand, p38[beta] is not expressed in differentiating erythroid progenitors. This is in contrast to nonhematopoietic tissues where p38[beta] appears almost universally expressed. Of interest, p38[delta] is expressed during the terminal phase of erythroid differentiation coinciding with the time when erythroid progenitors become erythropoietin independent and cease proliferation. (25) Additionally, p38 MAPK (p38[alpha]) is constitutively activated in low-grade myelodysplastic syndromes (MDSs) and its activation correlates with enhanced apoptosis in MDS bone marrows. (32-34) Using Western blot analysis with antibodies against each p38 isoform for humans, we recently demonstrated that all 4 isoforms ([alpha], [beta], [gamma], [delta]) of p38 MAPK were expressed by human RPMI8226 myeloma cell line (Figure 1, A). By reverse transcription-polymerase chain reaction, the plasma cells directly isolated from multiple myeloma (MM) patient samples (n = 6) using CD138 magnetic beads with AutoMACS (Miltenyi Biotech, Auburn, California) showed expression of messenger RNAs of all 4 isoforms of p38 MAPK (results from a representative case are shown in Figure 1, B). These findings suggest that differential expression of p38 isoforms may contribute to the progression of myeloma.
REGULATION OF p38 MAPK ISOFORM ACTIVATION (PHOSPHORYLATION)
Previous research has shown that the activation of particular p38 isoforms can be specifically controlled through different upstream regulators and coactivated by various combinations of these regulators. (35) MKK6 phosphorylates and strongly activates p38[alpha], p38[beta], and p38[gamma], whereas MKK3 activates p38[alpha] and p38[gamma] but not p38[beta]. MKK4 activates p38[alpha], weakly activates p38[gamma], and does not activate p38[beta] (Figure 2).
The phosphorylations of p38 isoforms are further differentially regulated depending on phosphatase levels. Under physiologic conditions, MAPK activation is often transient. Many dual-specificity phosphatases have been identified that act upon various members of the MAPK pathway and are grouped as the MAPK phosphatase family. Several members can efficiently dephosphorylate p38[alpha] and p38[beta] (36-38); however, p38[gamma] and p38[delta] are resistant to all known MAPK phosphatase family members. Additionally, other types of phosphatases such as serine/threonine protein phosphatase type 2C have been shown to have a role in downregulating the MAPK pathway. (39)
[FIGURE 2 OMITTED]
FUNCTION OF ACTIVATION (PHOSPHORYLATION) OF VARIOUS p38 MAPK ISOFORMS
Despite the substantial structural homology among the isoforms in each group, there is evidence that distinct isoforms exhibit different properties rather than just functional redundancy, although the detailed functions of each isoform remain largely unknown. (16,25) Furthermore, in some cases different isoforms may mediate opposing biologic responses to meet cellular requirements for various intricate and delicate biologic processing of stimulating signals. For example, in breast cancer cell lines, the p38[beta] isoform increases the activation of AP-1 transcriptional activities, whereas p38[gamma] and p38[delta] inhibit AP-1 transcriptional activities. Thus, AP-1-dependent cellular proliferation is simultaneously regulated by p38[beta], p38[gamma], and/or p38[delta] isoforms. These results suggest that an upstream signal of the p38 pathway is interpreted by the expression pattern p38 isoforms, leading to a specific cellular outcome dependent on the spectrum of p38 isoform expression. (40) For example, p38 activation would be stimulatory to the AP-1-dependent transcription if p38[beta] were the major form, whereas it would be inhibitory in cells predominantly expressing p38[gamma] and/or p38[delta].
Thus, the net response in cells expressing all p38 family members is determined by integrations of the positive and the negative regulatory signaling of various isoforms. Furthermore, the enhancing AP-1-dependent transcription effect of p38[beta] is kinase-dependent, because this effect is not seen with the transfection of phosphorylation-dead form p38[beta]/AF. But the inhibition by p38[gamma] and p38[delta] occurs regardless, whether the mutant or the wild-type forms of p38[beta] or p38[delta] is transfected. (40) The latter suggests that the inhibitory function may act through nonkinase functions of p38[gamma] and p38[beta] isoforms. Other studies have also suggested that p38[beta] may be mitogenic and/or antiapoptotic. In HeLa cells, for example, adenovirus-mediated p38[beta] delivery was demonstrated to protect SB202190-induced apoptosis. (41) Furthermore, p38[beta] but not p38[alpha] was shown to protect mesangial cells from TNF-[alpha]-induced apoptosis. (42) Recently, the activation of p38[alpha], but not other isoforms, was required for ras-induced invasion in NIH3T3 cells. (43)
In addition to the findings that each p38 family member has a distinct function, the biologic effects of each isoform may further depend on the individual cellular context. For example, inhibition of p38[gamma] suppressed [gamma]-radiation-induced [G.sub.2] arrest, whereas inhibition of other family members by the dominant negatives had no effect in human osteosarcoma U2OS cells. (44) In contrast, in PC12 cells (a pheochromocytoma cell line), inhibition of p38[alpha] and p38[gamma] counteracted hypoxia-induced [G.sub.0]/[G.sub.1] arrest by increasing cyclin D1 expression. (45) Another example is that green tea polyphenol selectively stimulated p38[delta] phosphorylation leading to the inhibition of AP-1 activity, which resulted in inhibiting cellular proliferation in human breast cancer cell lines. (40) In contrast, this stimulation activated AP-1, which led to cell proliferation in human keratinocytes as a result of simultaneous stimulation of the Ras/MEKK pathways. (46) Together, the p38 MAPK isoforms may lead to cell type-specific and stimulus-specific cellular responses by integrations of the positive and the negative regulatory signaling of various isoforms (Figure 3).
[FIGURE 3 OMITTED]
ROLES OF p38 MAPK AND ITS ISOFORMS IN CELL CYCLE AND APOPTOSIS
In fission yeast, StyI/Spc1, a homolog of p38 was required for recovery from a stress-induced cell cycle arrest. In mammalian cells, studies have suggested that p38 MAPK activity leads to inhibition of G1 progression via the repression of the cyclin D1 promoter, stabilization and transcriptional induction of p21 protein, and/or the regulation of p53 and RB expression. (12,47-50) Recent reports have also indicated that phosphorylation of p38 MAPK is required for the induction of cell cycle arrest in the G2 phase by ultraviolet light (51) and radiation. (44) This may be associated with the activation of p53, downregulation of cyclin A and B1 expression, or the persistent inhibitory phosphorylation of Cdc2 on Tyr15. (13-15) Nevertheless, the role of p38 isoforms in cell cycles remains largely unknown. Limited studies suggest that exogenous [alpha] and [beta], but not [gamma], isoforms of p38 delay progression into mitosis (52) and that the [alpha] and [gamma] isoforms of p38 have a role in [G.sub.2]-M transitions. (44,53)
p38 MAPK has previously been shown to mediate both proapoptotic (21,54) and antiapoptotic (55,56) signals in different systems, apparently depending on the stimulus and cell type involved. Although the precise mechanisms that account for the generation of such differential responses are unknown, one possibility is that they depend on the variable use of distinct isoforms. In mouse cardiomyocytes, transfection of p38[beta] enhanced cell survival (ie, antiapoptosis), whereas p38[alpha] increase cell death. (56) For its proapoptotic activity, phosphorylation of Bcl-2 family members by activated p38 MAPK has been shown to be a key event in the early induction of apoptosis under cellular stress. bcl-2 phosphorylation by p38[alpha] has been shown to be associated with a decrease in the antiapoptotic potential of bcl-2 protein, leading to caspase activation. Phosphorylation of Bax by activated p38 MAPK could initiate its mitochondria translocation prior to apoptosis. (57-60) Recently, a new p38 MAPK-regulated protein named p18 (Hamlet) was identified. p18 (Hamlet) accumulation requires the activation of p38 MAPK and p18 (Hamlet) phosphorylation by p38 MAPK is essential for its activity. It is demonstrated that p18 (Hamlet) interacts with p53 and stimulates the transcription of several proapoptotic p53 target genes such as PUMA and NOXA. (61) For antiapoptotic activity, increased expression of Bax, cIAP-1/2, XIAP, Smac/Diablo, and survivin has been suggested to be associated with p38 MAPK activation in some cell line models. (62-68) Furthermore, we have recently demonstrated that p38 MAPK activation induces phosphorylation of Hsp27 in MM cells leading to resistance to chemotherapeutic agents in myeloma. (69)
ROLE OF p38 MAPK IN REGULATING HEMATOPOIESIS AND MARROW FAILURE SYNDROMES
p38 MAPK plays a central role in maintaining the homeostasis of hematopoiesis by balancing, promoting, and inhibiting signals (Figure 4). It is well established that many cytokines and growth factors, including stem cell factor, IL-3, erythropoietin, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and thrombopoietin, regulate normal hematopoietic cell proliferation, survival, and differentiation by activating p38 MAPK pathways to generate their effects. (32,70-74) On the other hand, p38 MAPKs may also play critical roles in the production of hematopoietic growth factors. For example, studies have shown that disruption of p38[alpha] leads to decreasing erythropoietin gene expression in mice. (75) Therefore, p38 MAPK may be critical for developmental erythropoiesis via regulation of erythropoietin expression.
In addition to the activation by hematopoietic growth factors, p38 MAPK can be activated by cytokines that negatively regulate normal hematopoiesis, which include type I interferons (IFNs) (IFN-[alpha], IFN-[beta]). (71,73,76) It has been shown that these cytokines are potent inhibitors of the growth of hematopoietic progenitors of all 3 lineages, including erythroid, myeloid, and megakaryocytic lineage. Moreover, the p38 MAPK pathway, functioning in cooperation with the signal transducer and activation of transcription pathway, is required for regulation of type I IFN-dependent gene transcription. (77) Studies have shown that IFN-[alpha] and IFN-[beta] induce activation of a and p isoforms of p38 MAPK and its downstream effector MAPK activated protein kinase 2 in primary human erythroid progenitors. Furthermore, treatment of normal bone marrow cells with the p38 pharmacologic inhibitors SB203580 and SB202190 reverses the suppressive effects of type I IFNs on normal human hematopoiesis and restores the normal hematopoiesis in MDS hematopoietic cells. In addition to type I IFNs, p38[alpha] and p38[beta] are also activated in primitive human hematopoietic progenitors in response to transforming growth factor [beta] (TGF-[beta]), TNF-[alpha], and type II IFN (IFN-[gamma]) (78-80) treatment. We have recently shown that in the MDS population the -308A/A genotype of the TNF[alpha] gene and the TGF[beta]1 allele + 29T and genotype + 29T/T, each associated with higher levels of expression of TNF[alpha] and TGF[beta]1,were overrepresented, likely through the action of p38 MAPK contribute to the pathology of MDSs. (81) Notably, pharmacologic inhibitors of p38 MAPK reversed the inhibitory effects of these myelosuppressive cytokines on normal human hematopoiesis in vitro. In agreement with the in vitro observation, we have recently shown that the bone marrow samples obtained from patients with MDS markedly increased p38 MAPK activation by immunohistochemis try. (82)
[FIGURE 4 OMITTED]
Together these results indicate that p38 MAPK may act as a common signaling mediator for growth inhibitory signals generated by various myelosuppressive cytokines in addition to its role in promoting hematopoiesis via the growth factor. Imbalance of this bidirectional function of p38 MAPK toward the inhibitory side may play an important role in the pathogenesis of certain bone marrow failure syndromes (idiopathic aplastic anemia, paroxysmal nocturnal hemoglobinuria, or subsets of MDS), in which suppression of normal hematopoiesis results from overproduction of myelosuppressive cytokines. In the future, it will be of great interest to further dissect the function of each isoform in hematopoiesis.
ROLE OF p38 MAPK IN LEUKEMIAS
The roles of p38 MAPK in acute leukemia (myeloid and lymphocytic) have not been well established. There have been no studies demonstrating a role for constitutive activation of the p38 MAPK pathway in the pathophysiology of acute leukemias. However, p38 MAPK appears to play a role in drug sensitivity in leukemias. It has been shown that inhibition of p38 MAPK using the pharmacologic inhibitors (SB203580 or SB202190) enhances all-trans-retinoic acid--dependent induction of acute promyelocytic leukemia cell differentiation and all-trans-retinoic acid-dependent growth inhibition. (83) These findings indicate that the p38 MAPK pathway plays a negative role in the induction of all-trans-retinoic acid responses in acute promyelocytic leukemia and raises the possibility that combined use of all-trans-retinoic acid with pharmacologic inhibitors of p38 may prove more effective than ATRA alone. Similarly, treatment of NB-4 acute promyelocytic leukemia cells with arsenic trioxide also resulted in the activation of the p38/MAPK activated protein kinase 2 pathway, whereas pharmacologic inhibition of p38 further enhanced arsenic trioxide-induced apoptosis and growth inhibition of acute promyelocytic leukemia cells. (27,84) Additionally, the synergistic/additive effects of combining p38 MAPK inhibition and arsenic trioxide treatment have been seen in chronic myeloid leukemia (CML) (27) as well as myeloma cells recently shown by us. (69)
The p38 MAPK pathway has been shown to play roles in the pathogenesis and pathophysiology of CML. The RhoGEF domain of BCR can activate p38 and the function of p38 is required for BCR-regulated activation of nuclear factor-[kappa]B. Other studies have shown that the function of the p38 pathway is essential for the suppression of growth of CML cells by IFN-[alpha]. The IFN-[alpha] treatment of peripheral blood granulocytes from CML patients induces phosphorylation/activation of p38 in vitro and addition of pharmacologic inhibitors of p38 in CML bone marrow cultures reverses the suppressive effects of IFN-[alpha]. These results indicate that the activation of the p38 signaling cascade may be essential for the antileukemic effects of IFN-[alpha] in CML cells. (85-87)
The p38 pathway seems to play an important role in the effects of rituximab in chronic lymphocytic leukemia. p38 and its downstream effector, MAPK activated protein kinase 2, were activated during the culture of chronic lymphocytic leukemia cells with anti-CD20, whereas the treatment with the p38 pharmacologic inhibitor SB203580 resulted in the induction of apoptosis of the malignant lymphocytes. (88)
p38 MAPK PATHWAY IN LYMPHOMAS
Studies have suggested that the TNF-[alpha]--inducible proliferation of non-Hodgkin lymphoma cell lines depends on the activation of p38 MAPK. (89,90) Furthermore, it has also been demonstrated that p38 MAPK regulated TNF-[alpha] production. Therefore, p38 may both regulate TNF-[alpha] expression and mediate signals regulating growth of lymphoma cells upon its activation by TNF-[alpha]. (89,91)
The p38 MAPK pathways may also play roles in growth factors that promote cell proliferation of the malignant cells in Hodgkin lymphoma. Aberrant expression of c-Jun and JunB, downstream of p38 MAPK pathways, has been suggested to participate in the proliferation of Hodgkin lymphoma cells using cell line models. Constitutively activated AP-1 and overexpression of c-Jun and JunB were found in primary tumor cells from Hodgkin lymphoma patients. Finally, studies have shown that p38 is activated in Hodgkin lymphoma cell lines by the receptor activated nuclear factor-[kappa]B ligand, a factor regulating cytokine/chemokine secretion in Reed-Sternberg cells via autocrine mechanisms. (92,93)
p38 MAPKs IN MM
There is evidence that the p38 pathway indirectly promotes the growth of MM cells in response to growth factors of myeloma cells (such as IL-6, IL-10, insulin-like growth factor 1, and granulocytic colony-stimulating factor). A recent study demonstrated that a specific p38 MAPK inhibitor (VX-745) can inhibit IL-6 and vascular endothelial growth factor secretion in bone marrow stromal cells and that p38 MAPK inhibition blocks proliferation of MM cells upon contacting marrow stromal cells. (94,95) This is likely because p38 MAPK inhibition leads to inhibiting IL-6 secretion induced by adherence of malignant plasmacytes to bone marrow stromal cells, a major molecule for the survival and proliferation of myeloma cells. These results suggest that the p38 MAPK pathway is essential for paracrine secretion of IL-6 in MM bone marrows and also raises the possibility that targeting the p38 MAPK pathway and its specific isoforms may have therapeutic implications in the treatment of MM.
CONCLUSIONS AND FUTURE DIRECTIONS
p38 MAPK plays an important role in cell fate decision. It is shown to mediate a wide array of biologic responses, including regulation of cell cycle, apoptosis, and differentiation. In some hematologic systems, activation of p38 plays a key role of promoting or inhibiting hematopoietic growth with the former leading to hematologic malignancies and the latter resulting in marrow failure. Additionally, p38 activation may increase resistance to chemotherapeutic agents. The importance of different p38 isoforms in various cellular functions has been recently acknowledged. Further understanding of these isoforms will allow designing more specific inhibitors to target particular isoforms to maximize the treatment effect and minimize the side effects for treating hematopoietic malignancies.
We would like to express our deepest appreciation to Brandi Smith-Irving, MS, for her help of critically reading this manuscript. The work is support in part by a The Methodist Hospital Research Institute, Houston, Texas, and the Weill Medical College of Cornell University, New York, New York, collaborative grant to C.C.
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Yongdong Feng, MD, PhD; Jianguo Wen, PhD; Chung-Che (Jeff) Chang, MD, PhD
Accepted for publication January 13, 2009.
From the Department of Pathology, The Methodist Hospital and The Methodist Hospital Research Institute, Houston, Texas (Drs Feng, Wen, and Chang); the Department of Surgery, Tongji Hospital, Tongji Medical College in Huangzhong University of Science and Technology, Wuhan, P. R. China (Dr Feng); and the Department of Pathology, Weill Medical College of Cornell University, New York, New York (Dr Chang).
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Chung-Che (Jeff) Chang, MD, PhD, Department of Pathology, The Methodist Hospital and The Methodist Hospital Research Institute, 6565 Fannin, MS205, Houston, TX 77030 (e-mail: jeffchang@ tmhs.org).
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|Author:||Feng, Yongdong; Wen, Jianguo; Chang, Chung-Che|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Nov 1, 2009|
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