CD99 expression is positively regulated by Sp1 and is negatively regulated by Epstein-Barr virus latent membrane protein 1 through nuclear factor-κB

Lee, Im Soon; Kim, Min Kyung; Choi, Eun Young; Mehl, Anja; Jung, Kyeong Cheon; Gil, Myung Cheol; Rowe, Martin; Park, Seong Hoe

doi:10.1182/blood.v97.11.3596

Cited by 20 publications

(12 citation statements)

References 56 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…CD99 is expressed on most of human tissues and the significant role of CD99 in tumorigenesis was only documented in Hodgkin's disease, in which the loss of CD99 has been shown to play a critical role in the formation of Hodgkin's and Reed-Sternberg cells (29)(30)(31). The results from our study also suggest that the downregulation of CD99 type I could be associated with dedifferentiation of tumor cells in gastric adenocarcinomas.…”

Section: Discussionsupporting

confidence: 55%

Immunoreactivity of CD99 in Stomach Cancer

et al. 2002

Self Cite

View full text Add to dashboard Cite

Immunoreactivity of CD99 in Stomach CancerCD99 is characteristically expressed in Ewing's sarcoma/primitive neuroectodermal tumor. Recently its immunoreactivity has also been reported in other tumors. However, the significance of CD99 isoforms expressed in these tumors has not been elucidated. In this study, we evaluated the expression of CD99 isoforms and its relationship with histopathologic parameters in gastric adenocarcinomas. Paraffin sections of 46 gastric adenocarcinomas were stained with an anti-CD99 monoclonal antibody, YG32. Twelve (26.1%) cases of 46 gastric adenocarcinomas showed immunoreactivity to YG32. The CD99 expression was also seen both in non-neoplastic foveolar epithelial cells and infiltrating lymphocytes. In addition, Western blot and RT-PCR analyses revealed that the type I is the predominant isoform of CD99 in non-neoplastic and neoplastic gastric tissues. The CD99 expression was usually seen in the intestinal type adenocarcinoma, while rarely in the diffuse type. The CD99 immunoreactivity decreased in MMP-2-overexpressing adenocarcinomas (p=0.028). Our results suggest that the type I is the major isoform of CD99 expressed in non-neoplastic gastric mucosa and gastric adenocarcinomas and its downregulation in gastric adenocarcinoma may be associated with cellular dedifferentiation and/or MMP-2 overexpression.

show abstract

Section: Discussionsupporting

confidence: 55%

Immunoreactivity of CD99 in Stomach Cancer

et al. 2002

Self Cite

View full text Add to dashboard Cite

show abstract

“…Sp1 binds to six sites located in the region between Ϫ122 and Ϫ60 relative to the transcription initiation site of the p21 gene (45). The potential involvement of Sp1 in the LMP1-mediated repression of the p21 promoter is supported by the recent finding showing that LMP1 repressed the transcription driven by the promoter of the CD99 gene, which encodes for a protein that is involved in cell adhesion, differentiation, and apoptosis in T cells and neurons (46). The proximal promoter of the CD99 gene contains an Sp1 site, and this site appears to be indispensable for the repressive activity of LMP1 (46).…”

Section: Lmp1 Is An Inhibitor Of the Basal And Tgf␤-inducible Activitmentioning

confidence: 93%

Inhibition of Transforming Growth Factor β Signaling and Smad-dependent Activation of Transcription by the Latent Membrane Protein 1 of Epstein-Barr Virus

Prokova¹,

Mosialos²,

Kardassis³

2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Inhibition of transforming growth factor ␤ (TGF␤) signaling by the Epstein-Barr virus Latent Membrane Protein 1 (LMP1) may account, at least in part, for the oncogenic activity of LMP1. We found that LMP1 is a potent inhibitor of TGF␤ signaling and Smad-dependent activation of transcription in 293 epithelial cells and COS-7 fibroblasts. LMP1 strongly inhibited the uninduced and the Smad-inducible activity of the promoters of the human p21/WAF1/Cip1 gene and the mouse Smad7 gene. Inhibition of TGF␤ signaling and Smad-dependent activation of transcription by LMP1 was greatly reduced by deletion of both C-terminal activating regions 1 and 2 of LMP1 as well as by overexpression of a nondegradable form of IB. In contrast, specific inhibitors of p38 kinase or MEK kinase did not reverse the inhibitory activity of LMP1. TGF␤ signaling was enhanced by overexpression of dominant negative forms of the LMP1 effectors TRAF2, NIK, and IKK␤ and was abolished by overexpression of p65/RelA or a p50/p65 fusion protein.Deletion of the transactivation domain of p65 abolished its inhibitory activity. Immunoblotting and immunofluorescence microscopy indicated that suppression of TGF␤ signaling and Smad transcriptional activity by LMP1 was not due to Smad degradation or cytoplasmic retention suggesting that LMP1 affects the nuclear function of Smad proteins. Our data are consistent with an essential role of NF-B activation by LMP1 in the inhibition of TGF␤ signaling and Smad-mediated transcriptional responses.The latent membrane protein 1 (LMP1) 1 of Epstein-Barr virus (EBV) is the principal transforming antigen of the virus (1). LMP1 can transform rodent fibroblasts by causing loss of contact inhibition and anchorage-independent growth, and it plays an essential role in B lymphocyte growth transformation by EBV in vitro (2-4). Transgenic mice expressing LMP1 in B-lymphocytes develop lymphomas at a much greater frequency than non-transgenic littermates (5). Finally, LMP1 expression is tightly linked with the development of most human malignancies associated with EBV, including Hodgkin's disease, anaplastic nasopharyngeal carcinoma, and lymphoproliferative disease (6).LMP1 is a 386-amino acid integral membrane protein that consists of a 24-amino acid N-terminal cytoplasmic domain, six transmembrane domains connected by short reverse turns, and a 200-amino acid cytoplasmic C terminus (see Fig. 1A). The six transmembrane domains enable the protein to aggregate in plasma membrane patches, whereas the cytoplasmic C terminus plays an essential role in the communication of the protein with intracellular signaling modules. LMP1 resembles a constitutively active member of the tumor necrosis factor receptor superfamily, and its function overlaps significantly with that of CD40 (7-9). Signal transduction by LMP1 culminates in the activation of transcription factors NF-B, AP1, and STAT1/3 (9 -14). NF-B and AP1 activation have been associated with the transforming potential of LMP1. The domains of LMP1 (CTAR1 and CTAR2) that lead to NF-B and AP1 a...

show abstract

“…Recently, Grimm et al demonstrated that LMP1 inhibits Bax through a direct binding of p50/p65 heterodimer on the promoter (19). Alternatively, another NF-B-repressed target gene of LMP1, CD99, lacks a NF-B consensus sequence in its promoter, suggesting an indirect NF-B-mediated recruitment of corepressors or a squelching effect of coactivators (34). Lack of a NF-B binding element in the LMP1 promoter suggests that DNA binding of p65 is not required for the p65-mediated inhibition of pLMP1.…”

Section: Vol 80 2006 Lmp1 Autoactivation During Type II Latency 7389mentioning

confidence: 99%

“…This transactivation is further enhanced by two other latent proteins, EBNA-LP and EBNA3C (45,67). Alternatively, pLMP1 can be activated in an EBNA2-independent manner by several cellular proteins, including interferon regulatory factor 7 (IRF7) (42), STAT3 (7), Notch1 (22), Sp1 (34), USF, ATF1, and CREB1 (53). pLMP1 activity can also be inhibited by a Max-Mad1 and histone deacetylase (HDAC) complex (54).…”

mentioning

confidence: 99%

Autoactivation of the Epstein-Barr Virus Oncogenic Protein LMP1 during Type II Latency through Opposite Roles of the NF-κB and JNK Signaling Pathways

Goormachtigh

Ouk

Mougel

et al. 2006

J Virol

View full text Add to dashboard Cite

Epstein-Barr virus (EBV)is associated with several human malignancies where it expresses limited subsets of latent proteins. Of the latent proteins, latent membrane protein 1 (LMP1) is a potent transforming protein that constitutively induces multiple cell signaling pathways and contributes to EBV-associated oncogenesis. Regulation of LMP1 expression has been extensively described during the type III latency of EBV. Nevertheless, in the majority of EBV-associated tumors, the virus is commonly found to display a type II latency program in which it is still unknown which viral or cellular protein is really involved in maintaining LMP1 expression. Here, we demonstrate that LMP1 activates its own promoter pLMP1 through the JNK signaling pathway emerging from the TES2 domain. Our results also reveal that this activation is tightly controlled by LMP1, since pLMP1 is inhibited by LMP1-activated NF-B signaling pathway. By using our physiological models of EBV-infected cells displaying type II latency as well as lymphoblastoid cell lines expressing a type III latency, we also demonstrate that this balanced autoregulation of LMP1 is shared by both latency programs. Finally, we show that this autoactivation is the most important mechanism to maintain LMP1 expression during the type II latency program of EBV.Epstein-Barr virus (EBV) is a widespread herpesvirus, found in more than 90% of healthy adults and persisting, in the vast majority of individuals, as a lifelong and asymptomatic infection. EBV classically infects B cells, causing sometimes a benign disease (infectious mononucleosis) but also malignant disorders, such as B-lymphoproliferative diseases, in patients with severe immunodeficiency. In immunocompetent hosts, EBV is also associated with other malignancies, including Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, peripheral or nasal NK/T-cell lymphomas, and gastric, breast, and hepatocellular adenocarcinomas (46,50). In all EBV-associated tumors, the virus displays mainly a latency program of infection with a restricted pattern of gene expression, which can be classified in three types. Type I latency, during which only the EBV-encoded nuclear antigen 1 (EBNA1) is expressed, is found in Burkitt's lymphoma. Type II latency is characterized by coexpression of EBNA1 and latent membrane proteins LMP1, LMP2A, and LMP2B and is found in nasopharyngeal carcinoma, Hodgkin's disease, NK/T-cell lymphomas, and AIDS-related non-Hodgkin's lymphomas. Type III latency with expression of the five EBNAs and three latent membrane proteins is restricted to B lymphomas of immunodeficient patients (50).Cellular models allowing investigation of the roles of LMP1 during type II and type III latencies have been developed. In vitro, EBV can infect and immortalize resting B cells to yield permanent growth of lymphoblastoid cell lines (LCLs) displaying a full latency III program (27). We previously showed that EBV can also infect and transform T cells and monocytes. We have described and extensively characterized two cel...

show abstract

CD99 expression is positively regulated by Sp1 and is negatively regulated by Epstein-Barr virus latent membrane protein 1 through nuclear factor-κB

Abstract: Epstein-Barr virus (EBV)-

Cited by 20 publications

References 56 publications

Immunoreactivity of CD99 in Stomach Cancer

Immunoreactivity of CD99 in Stomach Cancer

Inhibition of Transforming Growth Factor β Signaling and Smad-dependent Activation of Transcription by the Latent Membrane Protein 1 of Epstein-Barr Virus

Autoactivation of the Epstein-Barr Virus Oncogenic Protein LMP1 during Type II Latency through Opposite Roles of the NF-κB and JNK Signaling Pathways

Contact Info

Product

Resources

About