Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Raf promotes human herpesvirus-8 (HHV-8/KSHV) infection

Abstract

Human herpesvirus-8 (HHV-8/KSHV) is etiologically associated with Kaposi's sarcoma (KS) and other tumors. Constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway has been associated with a variety of tumors, including AIDS-related KS. The oncoprotein Raf is situated at a pivotal position in regulating the MAPK pathway. Hence, we analysed the effect of oncoprotein Raf on HHV-8 infectious entry into target cells. Here we report Raf expression to significantly enhance HHV-8 infection of target cells. These findings implicate a role for Raf not only in the infectious entry of HHV-8 but also in modulating KS pathogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Ablashi DV, Chatlynne LG, Whitman Jr JE and Cesarman E . (2002). Clin. Microbiol. Rev., 15, 439–464.

  • Adams V, Kempf W, Hassam S, Briner J, Schmid M, Moos R and Pfaltz M . (1995). J. Med. Virol., 46, 189–193.

  • Akula SM, Naranatt PP, Walia NS, Wang FZ, Fegley B and Chandran B . (2003). J. Virol., 77, 7978–7990.

  • Akula SM, Pramod NP, Wang FZ and Chandran B . (2001a). Virology, 284, 235–249.

  • Akula SM, Pramod NP, Wang FZ and Chandran B . (2002). Cell, 108, 407–419.

  • Akula SM, Wang FZ, Vieira J and Chandran B . (2001b). Virology, 282, 245–255.

  • Aoki Y, Jones KD and Tosato G . (2000). Hematother. Stem Cell Res., 9, 137–145.

  • Aoki Y and Tosato G . (2001). Leuk. Lymphoma, 41, 229–237.

  • Bailer RT, Lazo A, Ng-Bautista CL, Hout BL, Ness GM, Hegtvedt AK, Blakeslee JR, Stephens RE, Brierley GP and Mallery SR . (1995). J. Interferon Cytokine Res., 15, 473–483.

  • Bairey O, Boycov O, Kaganovsky E, Zimra Y, Shaklai M and Rabizadeh E . (2004). Leuk. Res., 28, 243–248.

  • Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, Gutkind JS, Asch AS, Cesarman E, Gershengorn MC, Mesri EA and Gerhengorn MC . (1998). Nature, 391, 86–89.

  • Baumann B, Weber CK, Troppmair J, Whiteside S, Israel A, Rapp UR and Wirth T . (2000). Proc. Natl. Acad. Sci. USA, 97, 4615–4620.

  • Birkmann A, Mahr K, Ensser A, Yaguboglu S, Titgemeyer F, Fleckenstein B and Neipel F . (2001). J. Virol., 75, 11583–11593.

  • Blackbourn DJ, Lennette E, Klencke B, Moses A, Chandran B, Weinstein M, Glogan RG, Witte MH, Way DL, Kutzkey T, Herndier B and Levy JA . (2000). AIDS, 16, 1123–1133.

  • Blasig C, Zietz C, Haar B, Neipel F, Esser S, Brockmeyer NH, Tschachler E, Colombini S, Ensoli B and Surzl M . (1997). J. Virol., 71, 7963–7968.

  • Blotnick S, Peoples GE, Freeman MR, Eberlein TJ and Klagsbrun MT . (1994). Proc. Natl. Acad. Sci. USA, 91, 2890–2894.

  • Cerimele F, Curreli F, Ely S, Friedman-Kien AE, Cesarman E and Flore O . (2001). J. Virol., 75, 2435–2443.

  • Chandran B, Smith MS, Koelle DM, Corey L, Horvat R and Goldstein E . (1998). Virology, 243, 208–217.

  • Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM and Moore PS . (1994). Science, 266, 1865–1869.

  • Chang F and McCubrey JA . (2001). Oncogene, 20, 4354–4364.

  • Chong H, Vikis HG and Guan KL . (2003). Cell Signal., 15, 463–469.

  • Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JWC, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR and Futreal PA . (2002). Nature, 417, 949–953.

  • De Clercq E, Naesens L, De Bolle L, Schols D, Zhang Y and Neyts J . (2001). Rev. Med. Virol., 11, 381–395.

  • De Vos J, Couderc G, Tarte K, Jourdan M, Requirand G, Delteil MC, Rossi JF, Mechti N and Klein B . (2001). Blood, 98, 771–780.

  • Ellis PD, Hadfield KM, Pascall JC and Brown KD . (2001). Biochem. J., 15, 99–106.

  • Ensoli B, Sgadari C, Barillari G, Sirianni MC, Sturzl M and Monini P . (2001). Eur. J. Cancer, 37, 1251–1269.

  • Ensoli B, Sturzl M and Monini P . (2000). Semin. Cancer Biol., 10, 367–381.

  • Faris M, Ensoli B, Stahl N, Yancopoulos G, Nguyen A, Wang S and Nel AE . (1996). AIDS, 10, 369–378.

  • Gallo RC . (1998). Science, 282, 1837–1839.

  • Ganem D . (1998). Curr. Clin. Top. Infect. Dis., 18, 237–251.

  • Geraminejad P, Memar O, Aronson I, Rady PL, Hengge U and Tyring SK . (2002). J. Am. Acad. Dermatol., 47, 641–655.

  • Giraldo G, Beth E and Huang ES . (1980). Int. J. Cancer., 26, 23–29.

  • Gorden A, Osman I, Gai W, He D, Huang W, Davidson A, Houghton AN, Busam K and Polsky D . (2003). Cancer Res., 63, 3955–3957.

  • Hayward GS . (2003). Cancer Cell, 3, 1–3.

  • Hermouet S, Corre I, Gassin M and Sutton CA . (2003). N. Engl. J. Med., 348, 178–179.

  • Higashiyama S, Abraham JA, Miller J, Fiddes JC and Klagsbrun M . (1991). Science, 22, 936–939.

  • Higashiyama S, Iwamoto R, Goishi K, Raab G, Taniguchi N, Klagsbrun M and Mekada E . (1995). J. Cell. Biol., 128, 929–938.

  • Hilger RA, Schelulen ME and Strumberg D . (2002). Onkologie, 25, 511–518.

  • Hoyle PE, Moye PW, Steelman LS, Blalock WL, Franklin RA, Pearce M, Cherwinski H, Bosch E, McMahon M and McCubrey JA . (2000). Leukemia, 14, 642–656.

  • Iivanainen E, Nelimarkka L, Elenius V, Heikkinen SM, Junttila TT, Sihombing L, Sundvall M, Maatta JA, Laine VJ, Yla-Herttuala S, Higashiyama S, Alitalo K and Elenius K . (2003). FASEB J., 17, 1609–1621.

  • Ingram JL, Rice AB, Santos J, Van Houten B and Bonner JC . (2003). Am. J. Physiol. Lung Cell Mol. Physiol., 284, L774–L782.

  • Janssen RA, Veenstra KG, Jonaxch P, Jonaxch E and Mier JW . (1998). J. Biol. Chem., 273, 32182–32186.

  • Karkkainen MJ and Petrova TV . (2000). Oncogene, 19, 5598–5605.

  • Kempf W and Adams V . (1996). Biochem. Mol. Med., 58, 1–12.

  • Kolch W . (2000). Biochem. J., 351, 289–305.

  • Le Gall M, Chambard JC, Grall D and Van Obberghen-Schilling E . (2003). J. Cell Physiol., 196, 98–104.

  • Lee JT and McCubrey JA . (2002). Expert Opin. Ther. Targets, 6, 659–678.

  • Marshall CJ . (1996). Nature, 383, 127–128.

  • Masood R, Cesarman E, Smith DL, Gill PS and Flore O . (2002). Am. J. Pathol., 160, 23–29.

  • Masson-Gadais B, Houle F, Laferriere J and Huot J . (2003). Cell Stress Chaperones, 8, 37–52.

  • McCarthy SA, Chen D, Yang BS, Garcia Ramirez JJ, Cherwinski H, Ch XR, Klagsbrun M, Hauser CA, Ostrowski MC and McMahon M . (1997). Mol. Cell. Biol., 17, 2401–2412.

  • McCubrey JA, Steelman LS, Hoyle PE, Blalock WL, Weinstein-Oppenheimer C, Franklin RA, Cherwinski H, Bosch E and McMahon M . (1998). Leukemia, 12, 1903–1929.

  • Mercer KE and Pritchard CA . (2003). Biochim. Biophys. Acta, 1653, 25–40.

  • Monini P, Rotola A, de Lellis L, Corallini A, Secchiero P, Albini A, Benelli R, Parravicini C, Barbanti-Brodano G and Cassai E . (1996). Int. J. Cancer, 66, 717–722.

  • Morand P, Buisson M, Collandre H, Chanzy B, Genoulaz O, Bourgeat MJ, Pinel N, Leclercq P, Leroux D, Marechal V, Fritsch L, Ruigrok R and Seigneurin JM . (1999). Leuk. Lymphoma, 35, 379–387.

  • Myoung H, Hong SP, Yun PY, Lee JH and Kim MJ . (2003). Cancer Sci., 94, 215–220.

  • Naglich JG, Metherall JE, Russell DW and Eidels L . (1992). Cell, 69, 1051–1061.

  • Naranatt PP, Akula SM, Zien CZ, Krishnan HH and Chandran B . (2003). J. Virol., 77, 1524–1539.

  • Olayioye MA, Neve RM, Lane HA and Hynes NE . (2000). EMBO J., 9, 3159–3167.

  • Peyssonnaux C and Eychene A . (2001). Biol. Cell, 93, 53–62.

  • Planz O, Pleschka S and Ludwig S . (2001). J. Virol., 75, 4871–4877.

  • Popik W and Pitha PM . (1996). Mol. Cell. Biol., 16, 6532–6541.

  • Raab G, Higashiyama S, Hetelekidis S, Abraham JA, Damm D, Ono M and Klagsbrun M . (1994). Biochem. Biophys. Res. Commun., 204, 592–597.

  • Raab G and Klagsbrun M . (1997). Biochim. Biophys. Acta, 1333, F179–F199.

  • Russo JJ, Bohenzky RA, Chien MC, Chen J, Yan M, Maddalena D, Parry JP, Peruzzi D, Edelman IS, Chang Y and Moore PS . (1996). Proc. Natl. Acad. Sci. USA, 93, 14862–14867.

  • Samuels ML, Weber MJ, Bishop JM and McMahon M . (1993). Mol. Cell. Biol., 13, 6241–6252.

  • Sebolt-Leopold JS . (2000). Oncogene, 19, 6594–6599.

  • Shelton JG, Moye PW, Steelman LS, Blalock WL, Lee JT, Franklin RA, McMahon M and McCubrey JA . (2003). Leukemia, 17, 1765–1782.

  • Shen H, Clauss M, Ryan J, Schmidt AM, Tijburg P, Borden L, Connolly D, Stern D and Kao J . (1993). Blood, 81, 2767–2773.

  • Sirianni MC, Uccini S, Angeloni A, Faggioni A, Cottoni F and Ensoli B . (1997). Lancet, 349, 255.

  • Spear PG and Longnecker R . (2003). J. Virol., 77, 10179–10185.

  • Takenaka M, Hirade K, Tanabe K, Akamatsu S, Dohi S, Matsuno H and Kozawa O . (2003). Biochem. Biophys. Res. Commun., 301, 198–203.

  • Thompson SA, Higashiyamanll S, Wood K, Pollitt NS, Damm D, McEnroe G, Garrick B, Ashton N, Laus K, Hamock N, Klagsbrunll M and Abraham JA . (1994). J. Biol. Chem., 269, 2541–2549.

  • Tokuda H, Hatakeyama D, Akamatsu S, Tanabe K, Yoshida M, Shibata T and Kozawa O . (2003). Arch. Biochem. Biophys., 415, 117–125.

  • Vieira J, O'Hearn L, Kimball E, Chandran B and Corey L . (2001). J. Virol., 75, 1378–1386.

  • Wang FZ, Akula SM, Pramod NP, Zeng L and Chandran B . (2001). J. Virol., 75, 7517–7527.

  • Wang H and Keiser JA . (1998). Circ. Res., 83, 832–840.

  • Weinstein-Oppenheimer CR, Burrows C, Steelman LS and McCubrey JA . (2002). Cancer Biol. Ther., 1, 256–262.

  • Woods D, Cherwinski H, Venetsanakos E, Bhat A, Gysin S, Humbert M, Bray PF, Saylor VL and McMahon M . (2001). Mol. Cell. Biol., 21, 3192–3205.

  • Yang X, Chen Y and Gabuzda D . (1999). J. Virol., 73, 3460–3466.

  • Yang S, Toy K, Ingle G, Zlot C, Williams PM, Fuh G, Li B, de Vos A and Gerritsen ME . (2002). Arterioscler. Thromb. Vasc. Biol., 22, 1797–1803.

  • Yoshiizumi K, Yamamoto M, Miyasaka T, Ito Y, Kumihara H, Sawa M, Kiyoi T, Yamamoto T, Nakajima F, Hirayama R, Kondo H, Ishibushi E, Ohmoto H, Inoue Y and Yoshino K . (2003). Bioorg. Med. Chem., 11, 433–450.

  • Zhang L, Gasper WJ, Stass SA, Ioffe OB, Davis MA and Mixson AJ . (2002). Cancer Res., 62, 5463–5469.

  • Zhu L, Puri V and Chandran B . (1999). Virology, 262, 237–249.

Download references

Acknowledgements

SMA is the recipient of an institutional research grant from American Cancer Society (IRG-97-149). JAM is supported in part by NIH RO1CA098195. We thank Dr Jeffrey Vieira (Fred Hutchinson Cancer Research Center, Seattle, WA, USA) for GFP-HHV-8 (rKSHV.152) harboring BCBL-1 cells; Dr Martin McMahon (UCSF Comprehensive Cancer Center, San Francisco, CA, USA) for the various retrovirus constructs expressing Raf; Dr Phillip H Pekala, (Brody School of Medicine, Greenville, NC, USA) for the use of OLYMPUS IX50 inverted fluorescent microscope; Dr Vishnu Chintalgattu (Brody School of Medicine) for critically reading this manuscript; and Dr Adrian J Reber (University of Georgia, Athens) for his help with statistics.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shaw M Akula.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Akula, S., Ford, P., Whitman, A. et al. Raf promotes human herpesvirus-8 (HHV-8/KSHV) infection. Oncogene 23, 5227–5241 (2004). https://doi.org/10.1038/sj.onc.1207643

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207643

Keywords

This article is cited by

Search

Quick links