Human Immunodeficiency Virus-1 Tat 단백에 의한 인간 CD99유전자의 조절기전에 대한 연구 = Human Immunodeficiency Virus-l Tat Positively Regulates the Human CD99 Gene via DNA Demethylation

다국어 초록 (Multilingual Abstract)

HIV affects many organ systems. Patients with HIV infection have substantially increased risk of developing various cancers, primarily by opportunistic infection with oncogenic viruses due to their immunocompromised status. However, extensive evidence also indicates that the viral protein, Tat itself, may playas a major factor in the development of AIDS-related neoplasms. The molecular mechanism underlying Tat's oncogenic activity may include deregulation of cellular genes. Therefore, in this study, we examined the effect of HIV-l Tat on CD99 as one of the target cellular genes, which is a well-known tumor marker in several cancers. By using established HeLa clones that are stably expressing Tat, we found that CD99 is upregulated by endogenous Tat, whereas STAT3 is down regulated. Upon the screening of genes differentially expressed between Tat-stable cells and the control cells by using the gene fishing technique, DEG, we detected 3 genes which expression is affected by the presence of Tat. Furthermore, the methylation specific PCR analysis of the stably Tat expressing cell lines revealed that the CD99 promoter is de methylated in the presence of Tat. Taken together, these results open a potential role of CD99 in AIDS-related oncogenesis via epigenetic regulation by HIV-1 Tat.

참고문헌 (Reference)

1 Fittipaldi, A, "Transcellular protein transduction using the Tat protein of HIV-1" 57 : 597-608, 2005

2 Goedert, J.J., "Spectrum of AIDSassociated malignant disorders" 351 : 1833-1839, 1998

3 Brierley, M.M., "STATs : Multifaceted regulators of transcription" 25 : 733-744, 2005

4 Zhang, Q., "STAT3 induces transcription of DNA methyltransferase 1 (DNMT1) gene in malignant T-lymphocytes" 108 : 1058-1064, 2006

5 Ensoli, B., "Release, uptake, and effects of extracellular Human Immunodeficiency Virus type I Tat protein on cell growth and viral transactivation" 67 : 277-287, 1993

6 Kadin, M.E, "Pathology of Hodgkin's disease" 6 : 456-463, 1994

7 Verhoef, K., "Optimal Tat-mediated activation of the HIV-1 LTR promoter requires a full-length TAR RNA hairpin" 25 : 496-502, 1997

8 Huynh, D., "Oncogenic properties of HIV-Tat in colorectal cancer cells" 5 : 403-409, 2007

9 Corallini, A., "Inhibition of HIV-1 Tat activity correlates with down-regulation of bcl-2 and results in reduction of angiogenesis and oncogenicity" 299 : 1-7, 2002

10 Emerman, M., "HIV-1 regulatory/ accessory genes : Keys to unraveling viral and host cell biology" 280 : 1880-1884, 1998

11 Blazquez, M.V., "Extracellular HIV type 1 Tat protein induces CD69 expression through NF-kB activation : Possible correlation with cell surface Tat-binding proteins" 15 : 1209-1218, 1999

12 Farrell, P.J., "Epstein-Barr virus genes and cancer cells" 51 : 58-67, 1997

13 Evans, T.J., "Efficient EBV superinfection of group 1 Burkitt's lymphoma cells distinguishes requirements for expression of the Cp viral promoter and can activate the EBV productive cycle" 206 : 866-877, 1995

14 Robert, M.F., "DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells" 33 : 61-65, 2002

15 Lee, M.K., "DNA methylation dependent regulation of human CD99 expression in HRS cells of Hodgkin's lymphoma" 30 : 73-82, 2008

16 Marlo, A, "CpG island methylation is associated with transcriptional silencing of the tumor suppressor p16/ CDKN2/MTS1 in human cancers" 1 : 686-692, 1995

17 Serraino, D., "Cancer incidence in a cohort of HIV seroconverters. HIV Italian Seroconversion Study Group" 79 : 1004-1008, 1997

18 Sohn, H.W., "CD99 regulates the transport of MHC class I molecules from the golgi complex to the cell surface" 166 : 787-794, 2001

19 McArthur, C.P., "Amplification of extracellular matrix and oncogenes in tat-transfected human salivary gland cell lines with expression of laminin, fibronectin, collagens I, III, IV, c-myc and p53" 46 : 545-555, 2001

20 Aboulafia, D.M., "Acute myeloid leukemia in patients infected with HIV-1" 16 : 865-876, 2000