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Review
. 2004 Dec;85(6):305-19.
doi: 10.1111/j.0959-9673.2004.00407.x.

Regulation of growth signalling and cell cycle by Kaposi's sarcoma-associated herpesvirus genes

Shamindra Direkze  1 , Heike Laman
Affiliations
Review

Regulation of growth signalling and cell cycle by Kaposi's sarcoma-associated herpesvirus genes

Shamindra Direkze et al. Int J Exp Pathol. 2004 Dec.

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is the primary aetiological agent of at least three malignancies associated with HIV infection and immunosuppression: Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. KSHV encodes proteins that deregulate key checkpoints in the signalling pathways governing cell proliferation, which may ultimately contribute to the virus' oncogenic potential. To alter cellular signalling associated with proliferation, these viral proteins function like growth factor ligands/receptors, signal transduction proteins, transcription factors and cell cycle regulators. This review focuses on the mechanisms by which some KSHV-encoded proteins activate signalling pathways and cell proliferation and their role in the pathogenesis of KSHV-driven mechanisms.

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Figures

Figure 1
Figure 1
Enhanced interleukin-6 (IL-6) signalling by Kaposi's sarcoma-associated herpesvirus (KSHV) proteins. The presence of high serum levels of IL-6 is a characteristic of the KSHV-driven lymphomas and suggests that tumour cell proliferation is dependent on IL-6 signalling. KSHV proteins enhance IL-6 signalling, by direct and indirect mechanisms through their effects on the IL-6 receptor. Unlike its cellular counterpart, viral interleukin-6 (vIL-6) can directly initiate IL-6 signalling, independently of IL-6 receptor expression. Other KSHV proteins, viral G-protein-coupled receptor (vGPCR), vFLIP-1 and latency associated nuclear antigen-1 (LANA-1) induce transcriptional activation of the hIL-6 gene via JNK/SAPK and NF-κB pathways. In co-operation with vIL-6 expression from KSHV-infected cells, the high serum IL-6 contributes to enhanced signalling.
Figure 2
Figure 2
Regulation of the G1 cell cycle restriction point by Kaposi's sarcoma-associated herpesvirus (KSHV) proteins: Re-entry into cell cycle is regulated by the activity of the d-type cyclin/cdk complexes during the G1 phase of the cell cycle. Signalling from KSHV-encoded growth factor receptor ligands and signalling proteins culminate in the synthesis of D-type cyclins, which assemble with cdk4 or -6. Further, the viral interferon regulatory factor-1 (vIRF-1), viral interleukin-6 (vIL-6), latency associated nuclear antigen-1 (LANA-1) and vcyclin bypass or inhibit the cyclin-dependent kinase inhibitors (CDKIs) to enhance activity of the cellular cyclin/cdk complexes. CDKI-resistant vcyclin/cdk6 complexes phosphorylate and inactivate the retinoblastoma protein (pRb) to permit transcription of E2F-regulated genes and allow entry into S-phase. Rb inactivation is further augmented by LANA−1 interaction with Rb.
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