Gene Ther Mol Biol Vol 9, 51-60, 2005

 

Raf/MEK/ERK signaling: Implications in the infection and pathogenesis of viruses associated with AIDS

Review Article

 

Audy G. Whitman, Ossie F. Dyson, Patrick W. Ford, Shaw M. Akula*

Department of Microbiology & Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27834

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*Correspondence: Shaw M. Akula, Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA 27834; Tel: (252) 744-2702; Fax: (252) 744-3104; E-mail: akulas@mail.ecu.edu

Key words: KSHV, HHV-8, AIDS, Raf

Abbreviations: acquired immunodeficiency syndrome, (AIDS); basic fibroblast growth factor, (bFGF); Epstein-Barr virus, (EBV); growth factor, (GF); heparin binding-epidermal growth factor, (HB-EGF); hepatitis B virus, (HBV); hepatitis C virus, (HCV); human cytomegalovirus, (HCMV); human herpesvirus-6, (HHV-6); human herpesvirus-8, (HHV-8); human immunodeficiency virus, (HIV); human papillomavirus, (HPV); human T-cell lymphotropic virus, (HTLV); inflammatory cytokines, (IC); interferons, (IFN); interleukins, (IL); Kaposi's sarcoma-associated herpesvirus, (KSHV); monocyte chemoattractant protein-1, (MCP-1); placental growth factor, (PLGF), granulocyte-macrophage colony-stimulating factor, (GM-CSF), Granulocyte colony-stimulating factor, (G-CSF); tumor growth factor, (TGF); tumor necrosis factor, (TNF); vascular endothelial growth factor, (VEGF)

Received: 7 March 2005; Accepted: 15 March 2005; electronically published: April 2005

 

Summary

Acquired immunodeficiency syndrome (AIDS) is characterized by failure of the immune system that is overwhelmed by an organized and well orchestrated invasion by various opportunistic pathogens. Cancers associated with AIDS are predominantly caused by viruses. Oncoproteins are directly involved in the initiation of neoplastic transformation. Recently, the presence of activating mutations in Raf has been described in a variety of cancers. Raf expression enhances Kaposi's sarcoma-associated herpesvirus (KSHV) infection of cells. KSHV is an etiology for Kaposi's sarcoma (KS); a condition commonly associated with AIDS. In addition, Raf associated signaling also regulates expression of various growth factors (GFs)/inflammatory cytokines (ICs). Since, AIDS is a condition that is regulated by aberrant GF/IC expression, we analyzed a possible role for Raf expression in the infection and pathogenesis of AIDS associated viruses in this review. This review also attempts to rationalize on why Raf associated signaling could well be a novel target to treat disease conditions due to viruses associated with AIDS.

I. Introduction

Acquired immunodeficiency syndrome (AIDS) is one of the most destructive pandemics that is getting worse with the progression of time (UNAIDS report for 2003). Human immunodeficiency virus (HIV) infection results in the progressive deterioration of the immune system resulting in AIDS. AIDS is characterized by an immunodeficient condition, which helps to facilitate opportunistic infections by bacteria (Mycobacterium tuberculosis, Streptococcus pneumoniae, Salmonella enteritidis), fungi (Cryptococcus neoformans), parasites (protozoan parasites of the genus Plasmodium), and viruses [human papillomavirus (HPV), human T-cell lymphotropic virus (HTLV), human polyomavirus (BK and JC virus), hepatitis B virus (HBV), hepatitis C virus (HCV), human herpesvirus-6 (HHV-6), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus (KSHV)] (Holmes et al, 2003; Whitman et al, 2004). Of these, most cancers seen in AIDS setting are related to oncogenic viruses like those listed above (Aoki and Tosato, 2004). Pathogenesis mediated by the viruses associated with AIDS is reviewed in our earlier work (Whitman et al, 2004).

The first signaling pathway to be delineated was the Raf/MEK/ERK cascade. The extracellular signal-regulated kinase (ERK) constitutes a highly conserved signaling module that is activated in mammalian cells via stimulation of receptor tyrosine kinases, G-protein coupled receptors and integrins (Widmann et al, 1999). This signal cascade is broadly referred to as the mitogen activated protein (MAP) kinase (MAPK) module: Raf/MEK/ERK. This pathway regulates a variety of cellular processes, including embryogenesis, proliferation, differentiation and apoptosis, among others each of which plays a significant role in tumorigenesis (Hilger et al, 2002; Hindley and Kolch, 2002). However, deregulated Raf expression and activation as well as mutated forms of the Raf oncogenes have been observed in a wide variety of cancers (Davies et al, 2002; Rajagopalan et al, 2002). Over the last couple of years, our lab has been focusing on oncoprotein Raf and its role in KSHV infection of target cells and pathogenesis. There are several oncoproteins identified thus far: BCR-ABL, Bcl-2, Kit, Myc, Neu, Ras, Raf, Src, and others (Peles and Yarden, 1993; Grandori and Eisenman, 1997; Sawyers, 1997; Klasa et al, 2002; Kitamura and Hirotab, 2004; Martin, 2004; Wellbrock et al, 2004a). Initially, we decided to analyze the effect of Raf on KSHV infection of target cells due to the following reasons: (1) Raf has been identified as an oncogene playing a critical role in human cancers (Davies et al, 2002; Wellbrock et al, 2004b). B-Raf somatic missence mutations have been detected in malignant melanomas (66%) and colon cancers (15%) and at lower frequencies in a variety of human cancers (Davies et al, 2002). Raf proteins play a key role in the conserved Ras/Raf/MEK/ERK pathway, acting to relay signals from activated Ras proteins via MEK1/2 to ERK1/2, the key effectors of this pathway (Sebolt-Leopold, 2000), (2) a broad array of solid tumors are known to express constitutively phosphorylated ERK1/2 which is a downstream event of Ras/Raf signaling (Mercer and Pritchard, 2003), and (3) constitutive activation of the components (Ras/Raf) of the MAPK signaling pathway has been associated with a variety of tumors including AIDS-KS (Faris et al, 1996). It is almost two years since we started to work on Raf; very interesting findings have been identified and never ceases to amaze us. The purpose of this review is to summarize recent findings on the effects of Raf associated signaling in the infection and pathogenesis of viruses associated with AIDS. In addition, we also rationalize on why targeting Raf associated signaling may serve the purpose in controlling cancer induced by some of the viruses associated with AIDS.

II. Effect of Raf/MEK/ERK on virus infection and pathogenesis

A detailed description on Raf and its involvement in tumor formation was discussed previously (Whitman et al, 2004; Hamden et al, 2005). Viruses exploit the already available cellular signaling to their advantage; be it entry, infection, replication, or egress (Popik and Pitha, 2000; Hasler and Zouali, 2003; Hayward, 2004). Raf, and its associated signaling components Ras, MEK, and ERK, have been shown to aid in the infection and pathogenesis of viruses, including those associated with AIDS. The effects of Raf/MEK/ERK signaling on viruses associated with AIDS are described below:

A. HIV

HIV-1 infection predisposes to the development of specific types of cancer caused predominantly by EBV, KSHV, and HPV. HIV has a direct and/or indirect role to play in the development of cancers in AIDS patients by the above listed oncogenic viruses (Aoki and Tosato, 2004). Binding of HIV-1 to CD4 receptors is sufficient to stimulate the activation of Raf/MEK/ERK signaling in a Ras independent manner (Popik and Pitha, 1996; Popik et al, 1998). Binding of HIV-1 to CD4 receptors stimulate association of Lck with Raf-1 leading to the activation of the Raf associated signaling which eventually results in the expression of cytokine and chemokine genes. Interestingly, this process is independent of the Raf associated signaling induced by the stromal cell-derived factor 1 (SDF-1) binding CXCR4, which inhibits entry of T-cell-tropic HIV-1. In fact, SDF-1 binding to CXCR4 activates the Raf/MEK/ERK signaling but does not affect the CD4-mediated expression of cytokine and chemokine genes (Popik et al, 1998). Treatment of cells with MAPK stimulators, as well as coexpression of constitutively activated Ras, Raf, or MEK-enhanced HIV-1 infection of cells (Yang and Gabuzda, 1999). On the contrary, inhibition of the MAPK/ERK kinase pathways by dimethylamiloride lowered HIV infection of cells. The blocking of HIV-1 entry into target cells by dimethylamiloride indicates that HIV-1 uses macropinocytosis to enter endothelial cells (Liu et al, 2002). Recently, the same research group demonstrated that the MEK inhibitor, U0126 significantly inhibited the ERK1/2 phosphorylation initiated by HIV-1, gp120, or Tat in neonatal rat ventricular myocytes (NRVM) and coronary artery endothelial cells (CAEC) (Fiala et al, 2004). Other studies have shown target cells exposed to growth factors such as stromal cell-derived factor-1 (SDF-1) leads to an increased expression of the X4 strain of HIV-1 that is significantly inhibited by MEK inhibitors (Montes et al, 2000).

B. HBV and HCV

HBx protein of HBV has been reported to stimulate the Ras/Raf/MAPK cascade of signaling which may play a role in viral pathogenesis while, the HCV core protein activates the Ras/Raf signaling pathway independent of the entire viral machinery .

C. HCMV

HCMV is detected at a higher frequency in human tumor cells than it is in surrounding tissues. This is because, HCMV promotes cell survival by influencing tumor suppressor p53 and p73, and also by stimulation of the antiapoptotic Ras/Raf/MEK/ERK and PI-3K signaling pathways .

D. EBV

Activation of the Ras/Raf/MEK/ERK signaling pathway by EBV encoded latent membrane protein (LMP) is essential for transformation in fibroblasts (Roberts and Cooper, 1998).

E. KSHV

KSHV is also referred to as human herpesvirus-8 (HHV-8). KSHV is etiologically associated with all forms of Kaposi's sarcoma (KS), multicentric Castleman disease (MCD), and primary effusion lymphoma (PEL) (Chang et al, 1994; Ganem, 1998). Oncoprotein Raf enhances KSHV infection of target cells (Akula et al, 2004). In two separate studies, we demonstrated the ability of Raf/MEK/ERK signaling to induce vascular endothelial growth factor (VEGF) expression in cells (Ford et al, 2004; Hamden et al, 2004). Recently, we demonstrated that the Raf induced VEGF plays a critical role in mediating angiogenesis (Akula et al, 2005); a feature of all KSHV mediated pathogenesis (Gallo, 1998a; Ganem, 1998).

There is a dearth of knowledge on the effect of Raf associated signaling on HTLV-1, HPV, and HHV-6. This does not rule out a possible role for Raf in these virus infections. It should be remembered that the Raf associated signaling is not always essential for virus infection. Simian virus 40 (SV40) T antigen stimulates Raf signaling to transform both insect and mammalian cells (Raptis et al, 1997; Grammatikakis et al, 2001); however, SV40 binding to target cells does not activate Raf/MEK/ERK. Instead, binding of SV40 to target cells activate a tyrosine kinase and Ca2+-independent isoform of protein kinase C (PKC). SV40 infectious entry into cells was specifically and reversibly blocked by genistein (Dangoria et al, 1996). On the same lines, there are also instances where disruption of the Raf/MEK/ERK pathway has been demonstrated to aid in the infection of some viruses. Inhibition of MEK has been shown to up-regulate coxsackievirus and adenovirus receptors (CAR) expression in highly malignant cell lines. This specific disruption of the Raf/MEK/ERK pathway and increased expression of receptors enhances virus entry into the target cell (Anders et al, 2003).

III. Effect of growth factors (GFs)/inflammatory cytokines (ICs) on viral disease conditions

Growth Factors are serum proteins that regulate several cellular functions when they bind to specific cell-surface receptors. Growth factors mediate both the development as well as adaptive and pathological changes in the system (Waltenberger, 2005). Inflammatory Cytokines are chemical communicators between cells that regulate inflammatory responses and immune functions (Alfano and Poli, 2005). Pathogenesis is the cellular events and reactions that occur in the development of disease. Recent findings have suggested that upon infection, GFs and ICs are released by infected cells that promote infection of surrounding cells (Ganem, 1998; Aoki et al, 2000; Ensoli et al, 2000, 2001; Hayward, 2003; Hamden et al, 2005). Some examples of how GFs/ICs influence infection and pathogenesis of viruses associated with AIDS is listed below:

A. HIV

The hallmark of HIV-1 infection is a progressive dysfunction of the immune system, rendering the host vulnerable to a variety of opportunistic infections. Chronic HIV-1 infection leads to a virus-specific CD4(+) T-cell depletion accompanied by impaired antiviral cytotoxicity of CD8+ T cells. Dysregulation of GFs/ICs is considered to be one of the factors that contribute to such an aberrant cell-mediated immunity (Zhang et al, 2003; Granelli-Piperno et al, 2004; Lee et al, 2004; Shapshak et al, 2004). Several GFs/ICS play a role in the HIV-1 initiated dysfunction of immune system. Some examples are, (1) studies have demonstrated that the excessive secretion of interleukin-18 (IL-18) may promote HIV-1 replication and thus the disease progression (Wiercinska-Drapalo et al, 2004), and (2) recent studies have shown an elevated circulating levels of interleukin-7 (IL-7) but not interleukin-15 (IL-15), transforming growth factor-b (TGF-b ), and insulin-like growth factor-1 (IGF-1) during primary HIV-1 infection (Boulassel et al, 2004). Of these, IL-7 efficiently stimulates HIV-1 replication from CD8+ T cell/monocyte—depleted PBMCs when compared to IL-2 (Wang et al, 2005b). They also demonstrated that IL-7 showed a positive trend for inducing proviral reactivation from resting CD4+ T lymphocytes from HIV-1—infected patients on suppressive HAART.

B. HPV

ICs have been demonstrated to be released in response to HPV infection of the uterine cervix (Azar et al, 2004). Based on their results, they concluded that the detection of IL-10 and tumor necrosis factor-a (TNF-a ) in cervical secretions may be a useful indicator of the stage of HPV induced cervical lesions. Interleukin-10 is one of the cytokines that is commonly elevated in cervical dysplasias or carcinomas as well as in the cervix of HIV-positive individuals. Interestingly, IL-10 also seems to enhance persistence and progression of HPV related disease conditions (Arany et al, 2002).

C. HTLV-1

Angiogenesis is a determining factor for the growth of both solid and hematologic tumors. HTLV-1 transformed cells secrete high levels of VEGF and basic fibroblast growth factor (bFGF); both of which mediate angiogenesis (Merhi et al, 2001). In another study it was demonstrated that the HTLV-1 infected cells produced high concentrations of interferon gamma (INF-g ) which was critical for migration of such cells through the peripheral tissues and thus contribute directly to the inflammation and disease condition (Hanon et al, 2001).

D. Human polyomavirus

JC virus produces its pathogenesis under immunosuppressive states such as AIDS. During the pathogenesis of AIDS, HIV-infected microglia secrete cytokines including interleukin-1 (IL-1) and TNF-a , which affect neuronal cells resulting in dysfunction of the central nervous system. Studies demonstrated the involvement of IL-1b mediated up-regulation of the JC virus early promoter (Kim et al, 2004). In another study, it was demonstrated that the HIV Tat protein-induced TGF-b 1 augmented transcription of JCV promoter in glial cells (Enam et al, 2004).

E. HBV and HCV

GFs/ICs coordinate physiologic and pathologic processes going on in the liver and in pathogenesis mediated by HBV and HCV. A few examples of GF/IC mediated pathology are, (1) HBV encoded HBx may play a critical role in the hypoxia-induced angiogenesis through transcriptional activation of vascular endothelial growth factor (VEGF) during hepatocarcinogenesis (Lee et al, 2000), and (2) immunological studies demonstrate a vigorous cell-mediated immune response in HCV chronic liver disease and a deficient immune response in HBV chronic hepatitis (Missale et al, 1995).

F. HHV-6

HHV-6 is a potentially immunosuppressive agent that is suggested to act as a cofactor in the progression of HIV mediated disease conditions. Exposure of human macrophages to HHV-6 significantly lowered their ability to produce interleukin-12 (IL-12) (Smith et al, 2003). HHV-6 infection triggers monocytes to release monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10) (Arena et al, 2002). These findings implicate MCP-1 and IL-10 production to be closely related and that the marked level of MCP-1 is induced not only by the virus but also by virus-induced IL-10.

G. HCMV

EBV is the first human virus implicated in cancer. EBV utilizes its proteins in such a manner as to mimic several GFs, transcription factors, and antiapoptotic factors to control, regulate, and mediate its pathogenesis (Thompson and Kurzrock, 2004). BCRF1, BHRF1, and BARF1 are examples of important EBV encoded proteins that show sequence and functional homology to IL-10, BCL-2, and intracellular adhesion molecule 1, respectively (Thompson and Kurzrock, 2004). Latent membrane protein 1 (LMP-1) is one of the principle oncoproteins that is not only directly oncogenic but also can induce a broad range of GFs critical for the invasiveness of the cancers (Wakisaka and Pagano, 2003).

H. KSHV

KSHV pathogenesis is primarily dependent on the aberrant production of GFs/ICs (Gallo, 1998; Aoki and Tosato, 1999; Ensoli et al, 2001; Hayward, 2003). GFs/ICs play a major role in orchestrating several facets of KSHV pathogenesis such as activation of endothelial cells, recruitment of and activation of lymphocytes, mediating angiogenesis, vasculogenesis, and reactivation of latent infection (Gallo, 1998a). Some examples that best describe the role of GFs/ICs are, (1) IFN-g and oncostatin-M has been demonstrated to induce lytic cycle of KSHV replication (Chang et al, 2000; Mercader et al, 2000), and (2) bFGF acts synergistically with VEGF and influences cell growth, migration, differentiation, and angiogenesis. It is said to play a key role along with VEGF in the progression of tumor (Ensoli et al, 2001). In addition, we determined that GFs like VEGF and heparin-binding epidermal growth factor (HB-EGF) can enhance KSHV infection of cells (Akula et al, 2004; Hamden et al, 2004). We have previously discussed in detail on the role for GFs/ICs in KSHV mediated pathogenesis (Hamden et al, 2005).

IV. Targeting Raf/MEK/ERK: a novel strategy to counter cancers mediated by AIDS associated viruses

We propose targeting Raf/MEK/ERK signaling to be an effective and novel strategy to treat cancer mediated by AIDS associated viruses due to the following reasons,

(1) The role for Raf associated signaling is not extensively studied in virus research when compared to tumor biology. However, after the advent of success with the use of Raf and other signaling inhibitors in treating tumor conditions, there have been several reports and suggestions about treating virus infections by manipulating the cellular signaling pathways. Understanding virus induced/utilized signals may lead to successful strategies for targeting specific signaling molecules to develop anti-viral therapies. Recent studies have demonstrated that the drugs targeting the MAPK and ErbB-signaling pathways represent a promising new class of antiviral agents to treat SARS and poxvirus infections, respectively (Mizutani et al, 2004; Fauci and Challberg, 2005; Yang et al, 2005).

(2) Raf associated signaling seems to mediate virus infection and/or pathogenesis (section I).

(3) An elevated expression of Raf/MEK/ERK signaling is common among solid tumors (Mercer and Pritchard, 2003). In a recently concluded study we also demonstrated that the hematopoietic cells derived from KSHV infected primary effusion lymphoma (PEL) expressed elevated levels of Raf/MEK/ERK activity when compared to uninfected B cells (Akula et al, 2005).

(4) Drugs targeting signaling pathways such as Raf/MEK/ERK may be apt because of the decrease in possibility of the development of mutations that bestow resistance (Ferrara, 2004).

(5) Finally and more importantly, Raf holds a pivotal position in the MAPK signaling pathway (Hamden et al, 2005). Research has identified the ability of several other key signaling molecules (Ras, JAK, PKA, Rap, Src family kinase, Rac, PI3K, PDK-1, Akt) to transduce signaling via Raf; and interestingly, MEK seems to be one of the well characterized substrate for Raf resulting in the regulation of a variety of GFs/ICs expression (Hamden et al, 2005; Table 1).

All the above mentioned factors make the Raf/MEK/ERK a therapeutic target to cure disease conditions associated with a variety of AIDS related viruses (Hamden et al, 2005). There are several inhibitors specific for the Raf/MEK/ERK signaling pathway being tested for their ability to prevent cancers. Some of the popular Raf/MEK/ERK inhibitors are,

(1) BAY 43-9006 (Onyx Pharmaceuticals): The compound binds to the Raf substrate-binding cleft with a great affinity and blocks the ATP binding site. BAY 43-9006 is in phase III clinical trails for the treatment of various cancers (Lowinger et al, 2002; Strumberg and Seeber, 2005).

Table 1. Raf/MEK/ERK signaling regulates expression of GFs/ICs

GF/IC

Mechanism of the Raf/MEK/ERK mediated GF/IC expression

bFGF

Cyclic AMP-induced redirection of bFGF signaling is mediated via the Raf/MEK/ERK signaling pathway in glial cells (Bayatti and Engele, 2001).

G-CSF

NS-398, a selective COX 2 inhibitor, lowers G-CSF production via MAPK signaling pathway in lung cancer cell lines OKa-C-1 and MI-4 (Nakata et al, 2003). MEK inhibitors PD98059 and U0126 also allowed a full rescue of G-CSF-induced neutrophilic differentiation (Jorda et al, 2003).

GM-CSF

GM-CSF expression is induced by a new cytokine, ML-1 (IL-17F) through the activation of the Raf-1/MEK/ERK signaling pathway (Kawaguchi et al, 2004). MEK inhibitors reduce ERK cascade activation and thus preferentially inhibit GM-CSF production. They concluded that the activation of Raf/MEK/ERK leads to the up-regulation of GM-CSF expression in cells (Matsubara et al, 2005).

HB-EGF

Activation of Raf-1:ER and a conditional oncogenic form of B-Raf, delta B-Raf:ER, results in rapid induction of HB-EGF mRNA and secretion of mature HB-EGF from cells (Akula et al, 2004; McCarthy et al, 1995).

IL-1b

Activation of the MAPK pathway of signaling is involved in the A beta-induced expression of IL-1b , IL-8, and MCP-1 (Giri et al, 2003).

IL-6

It has been shown that Raf-1 is required for hematopoietic growth-factor-induced proliferation of murine cell lines, one of them being IL-6. This was concluded using c-raf antisense oligonucleotides to block Raf-1 (Muszynski et al, 1995). Histamine activates Ca2+-dependent PKC isoforms that activates the Raf/MEK/ERK cascades that leads to up-regulation of IL-6, and IL-8 (Matsubara et al, 2005).

IL-8

The Raf/MEK/ERK pathway is a necessity for the IL-8 expression induced by Adenovirus type 7; and this occurs at the level of transcription (Alcorn et al, 2001). Others have also reported that the Raf/MEK/ERK pathway is crucial for the activation of IL-8 (Matsubara et al, 2005).

IL-10

IL-10 levels in monocyte supernatant were inhibited by MEK inhibitors, PD98059 and Ro 09-2210 (van der Bruggen et al, 1999). Other studies have documented that the down-regulation and/or inactivation of the MAPK pathway is correlated with an up-regulation in IL-10 expression; as of now the exact phenomenon is not deciphered (Man et al, 2005).

IL-12

Candida albicans inhibits IL-12 production by human monocytes by secreting an ERK44/42 MAPK-stimulating factor and thus can attenuate effective immune responses (Tang et al, 2004).

IFN-g

The inhibition of the MEK/ERK pathway results in an enhanced, anti-proliferative effect of IFN-g (Romerio and Zella, 2002).

IFN-g

Raf kinase is a key mediator in T cell signaling crucial for the expression of IFN-g in Th1 cells (Webber et al, 1997).

MCP-1

Glycated human serum albumin was shown to stimulate IL-8 and MCP-1 production which was found to be predominately mediated by the MAPK signaling pathway (Bian et al, 2001). Another study reported that the ERK1/2 activation in THP-1 monocytes is involved in the expression of various GFs/ICs, including MCP-1 (Giri et al, 2003).

PlGF

There is little evidence on the direct role of Raf in PlGF expression. However, it should be noted that PlGF is a member of the VEGF family, and there is an abundant amount of data indicating that Raf regulates VEGF expression (Akula et al, 2004; Hamden et al, 2004; Weinstein-Oppenheimer et al, 2002).

TNF-a

In DC2.4 dendritic cells Raf is phosphorylated and involved in the production of TNF-b and tyrosine phosphorylation of P13-K via ERK (Nakayama et al, 2003).

TNF-b

In Jurkat cells or peripheral blood T lymphocytes, the p21 Ras/Raf/MEK-E1 cascade plays a role in regulating the production of TNF-b (Li et al, 1999).

TGF-b 1

MAPK inhibitor, such as PD98059, blocks the collaborative activities of RON and TGF-‚1 in alpha-SMA expression induction, thus demonstrating a regulating role of the MAPK pathway in the expression of TGF-b 1 (Wang et al, 2005).

VEGF

Overexpression of Raf in human foreskin fibroblasts induces expression of VEGF (Akula et al, 2004; Hamden et al, 2004). Other research has demonstrated that the disruption of the interaction between retinoblastoma tumor suppressor protein (Rb) and Raf-1 causes the inhibition of the VEGF-mediated capillary tubule formation (Dasgupta et al, 2004).

(2) Tyrphostin AG 879: The compound markedly inhibits the expression of the Raf-1 and HER-2 genes (Larsson, 2004).

(3) 17-AAG: An Hsp90 antagonist with a unique ability to inhibit multiple survival pathways, including Raf associated signaling (Rahmani et al, 2004). This is currently in phase I clinical trials (Neckers, 2002).

(4) ZM 336372: A protein kinase inhibitor that can specifically inhibit Raf kinase activity. It is still in preclinical stages of testing (Hill-Jackson et al, 1999).

(5) ISIS 5132: It is a 20-base anti-sense phosphorothioate oligodeoxyribonucleotide that specifically inhibits Raf-1 kinase activity. This has been found to be promising in phase II clinical trials (Gibbs, 2000).

(6) PD 184352 (CI-1040; Pfizer): It has been demonstrated to be well tolerated in phase I clinical trials (Allen et al, 2003). It inhibits phosphorylation of MEK1/2 by binding ATP and ERK1/2 binding sites on MEK1/2 (Lowinger et al, 2002).

(7) ARRY-142886 (AZD6244; AstraZeneca and Array BioPharma): It has been impressive in animal models for human cancers and is being proposed as one of the promising second generation MEK inhibitors. Interestingly, it is orally active, with a clean tolerability profile, and highly selective to MEK (Hamden et al, 2005).

V. Conclusion

At this point we are far from having completely understood Raf associated signaling and its influence on the cellular functions with respect to virus infection and pathogenesis. However, the role for Raf in tumor biology has been well documented. Raf signaling mediates tumor cell proliferation, cell migration, cell invasion, and angiogenesis; all of which are a hallmark of tumorigenesis (Bian et al, 2004; Wilhelm et al, 2004; Akula et al, 2005; Shin et al, 2005). Accordingly, Raf inhibitors have been used to treat various cancers that include breast cancer, lung adenomas, pancreatic cancer, thyroid cancer, and others (Kramer et al, 2004; Larsson, 2004; Sebolt-Leopold, 2004; Williams and Smallridge, 2004; Xiong, 2004). We are confident that the knowledge on the role of Raf/MEK/ERK signaling in virus mediated pathogenesis will grow substantially and that it can be used in the future to treat infection/pathogenesis mediated by viruses related to AIDS.

Acknowledgments

The work was supported in part by an Institutional Grant from American Cancer Society (IRG-97-149) to SMA. We thank Dr. Vishnu Chintalgattu and Balaji M. Akula for critically reading this manuscript. We also thank a past member of the lab, Khalief E. Hamden for his insightful discussion and sharing of ideas.

 

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Shaw M. Akula