Expression of human immunodeficiency virus type I tat results in down-regulation of bcl-2 and induction of apoptosis in hematopoietic cells.
Infection by human immunodeficiency virus type 1 (HIV-1) is characterized by progressive loss of various cell types, mainly CD4+ T lymphocytes. While a passive role for the virus in cell destruction is recognized, it does not account for the vast amount of cell death including those of uninfected "bystander' cells. Since in the past we and others have demonstrated the capacity of the Tat protein of HIV-1 to modulate the expression of various cellular genes and that Tat secreted by HIV-infected cells can be readily taken up by various cell types, we have investigated the role of Tat on inducing apoptosis. Our results indicate that T lymphocytes transfected to constitutively express HIV-1 tat, when grown under serum-free conditions results in rapid apoptosis characterized by typical ultrastructural features and DNA fragmentation. Additionally, we observed that in several hematopoietic cell types, including T and B lymphoid cells and monocytoid cells, the expression of HIV-1 tat results in down-regulation of bcl-2, an oncogene with known potential for inhibition of apoptosis. The tat-mediated down-regulation of bcl-2 was observed at both the transcriptional and translational levels. Also, tat-transfected cells expressed increased amounts of bax, a bcl-2 family protein known to induce apoptosis. While these results support reports in the literature of an active role for tat in inducing cell death in HIV-infected individuals, they point to a new mechanism involving Tat-mediated modulation of bcl-2 and bax.
Sastry
K J
KJ
Department of Veterinary Sciences, University of Texas MD Anderson Cancer Center, Bastrop 78602, USA.
Marin
M C
MC
Nehete
P N
PN
McConnell
K
K
el-Naggar
A K
AK
McDonnell
T J
TJ
D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D015536:Down-Regulation / Q000502:physiology*; D015696:Gene Products, tat / Q000378:metabolism / Q000502:physiology*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
C494826:BAX protein, human; D016895:Culture Media, Serum-Free; D015696:Gene Products, tat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D054322:tat Gene Products, Human Immunodeficiency Virus