Alteration in the Coding Potential and Expression of H-ras in Human Cytomegalovirus-Transformed Cells

Boldogh, István; Huang, Eng Shang; Rady, Peter; Arany, István; Tyring, Stephen K.; Albrecht, Thomas

doi:10.1159/000150396

Cited by 14 publications

(8 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a similar vein, Boldogh et al (47) have shown that three different cell lines transformed by HCMV infection harbor an activating mutation in both alleles in H-Ras. However, in both of these cases it is unclear whether the mutations in H-Ras or p53 are a direct result of the mutagenic activity of HCMV gene products.…”

Section: Discussionmentioning

confidence: 82%

Human cytomegalovirus IE1 and IE2 proteins are mutagenic and mediate “hit-and-run” oncogenic transformation in cooperation with the adenovirus E1A proteins

Shen

Zhu²,

Shenk

1997

Proc. Natl. Acad. Sci. U.S.A.

164

109

View full text Add to dashboard Cite

Some epidemiological studies have suggested a possible link between human cytomegalovirus (HCMV) infection and various malignancies, and HCMV has been shown to transform cultured cells. However, viral DNA is not detected in most transformants, and the mechanism by which HCMV might contribute to oncogenesis has remained obscure. Here we show that the HCMV immediate early 1 and 2 genes can cooperate with the adenovirus E1A gene to generate transformed foci of primary baby rat kidney cells. HCMV gene expression is transient and viral DNA is not present in clonal cell lines derived from the transformed foci. We find that the HCMV immediate early proteins are mutagenic, and we propose that HCMV has the potential to contribute to oncogenesis through a ''hit-and-run'' mechanism, by inducing mutations in cellular genes.Serological and molecular studies have suggested a possible association of human cytomegalovirus (HCMV) with the development of human malignancies, including cervical carcinoma, colon carcinoma, and prostate cancer (reviewed in refs. 1-5). A variety of laboratory observations demonstrate that HCMV has oncogenic potential, supporting the idea that HCMV might contribute to the induction of human tumors. HCMV has been shown to induce cervical neoplasia in mice (6), it can morphologically transform human (7,8) as well as other mammalian (9 -11) cells in culture, and HCMVtransformed cells can form tumors in experimental animals (6,8). In vitro assays have identified three regions on the HCMV genome with transforming activity (reviewed in ref. 5). However, if HCMV infection does contribute to tumor induction in humans, the mechanism underlying HCMV-induced oncogenesis is very likely different from that of DNA viruses that are known to play a role in human malignancies. Whereas specific viral genes are present and expressed in tumors induced by agents such as Epstein-Barr virus and the human papillomaviruses, no specific HCMV DNA sequence element is reliably present and often no viral DNA can be detected in cells transformed by HCMV (reviewed in refs. 4 and 12).We have previously reported (13) that the two most abundantly expressed immediate-early gene products of HCMV, IE1 and IE2 (reviewed in ref. 14), inhibit the induction of apoptosis by tumor necrosis factor ␣ (TNF-␣) or the adenovirus E1A oncoproteins. The fact that the IE1 and IE2 gene products are able to inhibit apoptosis raised the interesting possibility that they might cooperate with the adenovirus E1A oncoproteins to transform primary rodent cells, as do the adenovirus E1B 19-kDa (E1B) protein and the cellular Bcl-2 protein, each of which can block apoptosis (15,16). In this report, we show that the IE1 and IE2 gene products can, indeed, cooperate with E1A to transform primary baby rat kidney (BRK) cells. Unexpectedly, however, we find that expression of the IE1 and IE2 proteins is transient; HCMV proteins and DNA are not present in transformed cell lines derived from the foci. The IE1 and IE2 gene products are mutagenic, and we propose that...

show abstract

Section: Discussionmentioning

confidence: 82%

Human cytomegalovirus IE1 and IE2 proteins are mutagenic and mediate “hit-and-run” oncogenic transformation in cooperation with the adenovirus E1A proteins

Shen

Zhu²,

Shenk

1997

Proc. Natl. Acad. Sci. U.S.A.

164

109

View full text Add to dashboard Cite

show abstract

“…In the case of HCMV infection, a number of other mechanisms such as stimulation of growth factors or proto-oncogenes and inhibition of cellular apoptotic pathways may play a role in altering cell growth. Boldogh et al (11)(12)(13)(14)18) have demonstrated that HCMV infection activated a number of proto-oncogenes, such as c-myc, c-fos, and c-jun, and signaltransducing proteins such as H-ras. Jault et al (83) have shown that HCMV infection also resulted in the activation of a number of cell cycle-regulatory proteins such as p53, phosphorylated Rb, and cyclins.…”

Section: Resultsmentioning

confidence: 99%

Human Cytomegalovirus and Human Herpesvirus 6 Genes That Transform and Transactivate

1999

View full text Add to dashboard Cite

SUMMARY This review is an update on the transforming genes of human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6). Both viruses have been implicated in the etiology of several human cancers. In particular, HCMV has been associated with cervical carcinoma and adenocarcinomas of the prostate and colon. In vitro transformation studies have established three HCMV morphologic transforming regions (mtr), i.e., mtrI, mtrII, and mtrIII. Of these, only mtrII (UL111A) is retained and expressed in both transformed and tumor-derived cells. The transforming and tumorigenic activities of the mtrII oncogene were localized to an open reading frame (ORF) encoding a 79-amino-acid (aa) protein. Furthermore, mtrII protein bound to the tumor suppressor protein p53 and inhibited its ability to transactivate a p53-responsive promoter. In additional studies, the HCMV immediate-early protein IE86 (IE2; UL122) was found to interact with cell cycle-regulatory proteins such as p53 and Rb. However, IE86 exhibited transforming activity in vitro only in cooperation with adenovirus E1A. HHV-6 is a T-cell-tropic virus associated with AIDS-related and other lymphoid malignancies. In vitro studies identified three transforming fragments, i.e., SalI-L, ZVB70, and ZVH14. Of these, only SalI-L (DR7) was retained in transformed and tumor-derived cells. The transforming and tumorigenic activities of SalI-L have been localized to a 357-aa ORF-1 protein. The ORF-1 protein was expressed in transformed cells and, like HCMV mtrII, bound to p53 and inhibited its ability to transactivate a p53-responsive promoter. HHV-6 has also been proposed to be a cofactor in AIDS because both HHV-6 and human immunodeficiency virus type 1 (HIV-1) have been demonstrated to coinfect human CD4+ T cells, causing accelerated cytopathic effects. Interestingly, like the transforming proteins of DNA tumor viruses such as simian virus 40 and adenovirus, ORF-1 was also a transactivator and specifically up-regulated the HIV-1 long terminal repeat when cotransfected into CD4+ T cells. Finally, based on the interactions of HCMV and HHV-6 transforming proteins with tumor suppressor proteins, a scheme is proposed for their role in oncogenesis.

show abstract

“…The blotted RNA was analyzed using oligonucleotide probes to IFN-y (Clontech, Palo Alto, CA) or to a reference gene (G3PDH; Clontech). The oligonucleotides were labeled and the hybridizations were undertaken as described previously (25).…”

Section: Methodsmentioning

confidence: 99%

“…(24). The abundance of PCR products bound to the membranes was analyzed by hybridization (25) to [32P]labeled oligonucleotide probes (specific activities were between 6.4 and 7.8 cpm/pmol) for target (IFN-y) and reference (G3PDH) genes (Clontech). The levels of hybridization were visualized by autoradiography.…”

Section: Methodsmentioning

confidence: 99%

Novel Activation of -Interferon in Nonimmune Cells during Human Cytomegalovirus Replication

Boldogh¹,

Bui²,

Szaniszlo³

et al. 1997

Experimental Biology and Medicine

Self Cite

View full text Add to dashboard Cite

This is the first study documenting the induction of gamma-interferon (IFN-gamma) in human embryonic fibroblasts during human cytomegalovirus (HCMV) replication. Infection of cells with HCMV resulted in the consistent production of IFN-gamma RNA, as determined by RT-PCR and Northern blot analysis. Western blot analysis of cell lysates and immunoprecipitates from the cultural fluids of infected cells demonstrated the presence of IFN-gamma at the protein level. Induction of IFN-gamma required infectious HCMV, since high-dose ultraviolet inactivation of the virus stock eliminated IFN-gamma production. Further, IFN-gamma induction appears to be a late event in the virus replication cycle, since inhibition of HCMV DNA synthesis (e.g., phosphonoacetic acid) blocked the increase in IFN-gamma. Soluble factor(s) released from HCMV-infected cells apparently did not contribute to the induction of IFN-gamma, since virus stocks from which virus had been removed by sedimentation did not induce production of IFN-gamma. The appearance of IFN-gamma at late stages of HCMV infection and its elimination in the presence of an inhibitor (Actinomycin D) of RNA synthesis indicate a true transcriptional induction of this lymphokine at the RNA and protein levels. The significance of IFN-gamma production with regard to the replication and pathogenesis of HCMV in vitro and in vivo will require further investigation.

show abstract

Alteration in the Coding Potential and Expression of H-ras in Human Cytomegalovirus-Transformed Cells

Cited by 14 publications

References 25 publications

Human cytomegalovirus IE1 and IE2 proteins are mutagenic and mediate “hit-and-run” oncogenic transformation in cooperation with the adenovirus E1A proteins

Human cytomegalovirus IE1 and IE2 proteins are mutagenic and mediate “hit-and-run” oncogenic transformation in cooperation with the adenovirus E1A proteins

Human Cytomegalovirus and Human Herpesvirus 6 Genes That Transform and Transactivate

Novel Activation of -Interferon in Nonimmune Cells during Human Cytomegalovirus Replication

Contact Info

Product

Resources

About