ERK1/2 and MEK1/2 Induced by Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Early during Infection of Target Cells Are Essential for Expression of Viral Genes and for Establishment of Infection

Sharma-Walia, Neelam; Krishnan, Harinivas H.; Naranatt, Pramod P.; Zeng, Ling; Smith, Marilyn S.; Chandran, Bala

doi:10.1128/jvi.79.16.10308-10329.2005

Cited by 162 publications

(262 citation statements)

References 71 publications

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“…Since Erk-activation could be inhibited by HNMPA, our data further suggest that Erk activation in latently infected cells is largely due to activation of the IR. In addition, it has been shown that the Erk pathway is activated by KSHV during de novo infection to modulate initial gene cellular and viral expression (Sharma-Walia et al, 2005). PI3K is also activated early in KSHV infection (Sharma-Walia et al, 2005), while we did not see PI3K activation in latently infected cells since there was no change in AKT phosphorylation in KSHV infected E-DMVEC (Figure 7).…”

Section: Discussionmentioning

confidence: 68%

The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma

Rose

Carroll

et al. 2006

Oncogene

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Section: Discussionmentioning

confidence: 68%

The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma

Rose

Carroll

et al. 2006

Oncogene

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“…Structural analysis of purified virions of other herpesviruses, including HSV, CMV, EBV, and rhesus rhadinovirus, indicate that the conserved protein kinases of these viruses are also incorporated into mature virus particles (2,12,37,50,52). This finding suggests that this kinase may play a role in phosphorylating viral proteins during virion assembly and/or regulate the functions of viral and cellular proteins upon entry into host cells and during the early stage of de novo infection (47).…”

Section: Discussionmentioning

confidence: 78%

Kaposi's Sarcoma-Associated Herpesvirus-Encoded Protein Kinase and Its Interaction with K-bZIP

Izumiya

Geelen

et al. 2007

J Virol

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The oncogenic herpesvirus, Kaposi's sarcoma-associated herpesvirus, also identified as human herpesvirus 8, contains genes producing proteins that control transcription and influence cell signaling. Open reading frame 36 (ORF36) of this virus encodes a serine/threonine protein kinase, which is designated the viral protein kinase (vPK). Our recent efforts to elucidate the role of vPK in the viral life cycle have focused on identifying viral protein substrates and determining the effects of vPK-mediated phosphorylation on specific steps in viral replication. The vPK gene was transcribed into 4.2-kb and 3.6-kb mRNAs during the early and late phases of viral reactivation. vPK is colocalized with viral DNA replication/transcription compartments as marked by a polymerase processivity factor, and K-bZIP, a protein known to bind the viral DNA replication origin (Ori-Lyt) and to regulate viral transcription. The vPK physically associated with and strongly phosphorylated K-bZIP at threonine 111, a site also recognized by the cyclin-dependent kinase Cdk2. Both K-bZIP and vPK were corecruited to viral promoters targeted by K-bZIP as well as to the Ori-Lyt region. Phosphorylation of K-bZIP by vPK had a negative impact on K-bZIP transcription repression activity. The extent of posttranslational modification of K-bZIP by sumoylation, a process that influences its repression function, was decreased by vPK phosphorylation at threonine 111. Our data thus identify a new role of vPK as a modulator of viral transcription.Kaposi's sarcoma-associated herpesvirus (KSHV), also designated human herpesvirus 8, has been linked to several malignancies, including Kaposi's sarcoma, B-cell lymphomas, primary effusion lymphomas, and multicentric Castleman's disease in immunocompromised individuals (reviewed in reference 46). Kaposi's sarcoma is the most common malignancy associated with AIDS (45). The viral genome is doublestranded DNA, approximately 165 kbp, and encodes over 81 open reading frames (ORFs) (43). The majority of the ORFs are essential for viral replication and include genes necessary for viral DNA replication, transcription, and assembly of infectious particles (51). In addition, the KSHV genome contains a large number of ORFs with homology to known cellular genes. Several of these viral ORFs are implicated in modulating host immune responses, promoting angiogenesis, and dysregulating cell growth (14). A model for regulated expression of KSHV genes has been deduced from numerous genetic and biochemical studies of viral RNA patterns and activities of viral transactivators (22,31,39,49). As for other herpesviruses, KSHV genes in productive infection have been classified into the following temporally distinct classes: immediate-early, early, and late. This virus can also establish a latent state that is characterized by presence of a multicopy circular episome of viral DNA, which expresses a small subset of viral proteins. Productive (lytic) viral replication can be induced by treatment of latently infected cell lines with butyrate,...

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“…3C; upper panel), which indicated that the exogenously transfected mir-143 precursor miRNAs caused the decreased expression of the ERK5 protein at the translational level. The level of c-myc protein, a downstream signal protein of ERK5 (13,14), was also reduced after the transfection ( Fig. 3C; lower panel).…”

Section: Resultsmentioning

confidence: 89%

“…Thus, in the case of the signal molecules in the MAPK system and transcription factors targeted by such an miRNA, the expression of many proteins would be affected, leading to deregulation of the signal transduction of cell growth, survival and death. c-myc is also lowered by the transfection of cells with mir-143 precursor miRNAs, perhaps due to the decreased expression of ERK5, because c-myc lies downstream of the cell growth signaling pathway including ERK5 (13,14).…”

Section: Discussionmentioning

confidence: 99%

“…We also obtained a similar result from the transfection experiments using mir-143 precursor miRNAs. ERK5 is known to promote cell growth and proliferation in response to tyrosine kinase (13,14), therefore persistent dereased levels of mir-143 in cancer cells may be directly involved in carcinogenesis through activation of the mitogen-activated protein kinase (MAPK) cascade via ERK5. According to the target proteins of mir-145, although we searched for its several candidate proteins by Western blot, we could not determine it.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNAs 143 and 145 are possible common onco-microRNAs in human cancers

Akao¹,

2006

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Abstract. MicroRNAs (miRNAs) are endogenously expressed RNAs 18-24 nucleotides in length that regulate gene expression through translational repression by binding to a target mRNA. It is thought that the expression level of miRNAs, which act like antioncogenes, is frequently reduced in cancers because of chromosome deletion and epigenetic changes. Since the processing of miRNAs has been characterized to be enzymatic in nature, the expression levels of miRNAs are closely associated with the activity and levels of such enzymes. Here, we found that miRNA 143 and 145 expression levels were extremely reduced in colon cancer cells and commonly in the other kinds of cancer cells tested. The transfection of each precursor miRNA into the cells demonstrated a significant growth inhibition in human colon cancer DLD-1 and SW480 cells, and ERK5 was determined to be the target gene of miRNA 143. Since the presence of genomic loci of the miRNAs was confirmed by PCR in the cell lines and the precursor miRNAs exhibited a growth inhibitory effect in DLD-1 and SW480 cells, the early processes such as transcription and enzymatic modification from primary miRNAs to precursor miRNAs seemed to be commonly disturbed. These findings indicate that the miRNAs 143 and 145 could become good tumor markers and provide an important clue in the study of the mechanism of oncogenesis involving miRNAs.

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ERK1/2 and MEK1/2 Induced by Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Early during Infection of Target Cells Are Essential for Expression of Viral Genes and for Establishment of Infection

Cited by 162 publications

References 71 publications

The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma

The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma

Kaposi's Sarcoma-Associated Herpesvirus-Encoded Protein Kinase and Its Interaction with K-bZIP

MicroRNAs 143 and 145 are possible common onco-microRNAs in human cancers

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