Putative molecular mechanisms involved in HIV-1 TAT-mediated hematopoietic dysfunction in K562 cells
Description
HIV related cytopenias and bone marrow abnormalities have been linked to the HIV-1 Tat protein. Our previously published studies show that HIV-1 Tat administration substantially inhibits butyrate induced erythroid differentiation of the multipotent K562 cell line. To further delineate the effects of Tat on hematopoietic differentiation, we studied the effects of HIV Tat on megakaryocytopoiesis. Our studies reveal that Tat potentiates the PMA-induced megakaryocytic differentiation of K562 cells as ascertained by 3H serotonin uptake and CD61 cell surface expression. As Tat protein has been shown to induce the activity of endogenous host transcription factors, we investigated the effects of Tat on the activity and expression of several transcriptional effectors known to be involved in hematopoiesis. Our studies reveal that Tat conditionally modulates the transcriptional activity of cAMP response element binding protein (CREB) binding protein (CBP), as well as CBP-mediated histone acetylation. Furthermore, we found that Tat protein induced the transient expression CBP. Since CBP interacts with multiple transcription factors, studied the effects of Tat protein on the expression and function of CBP dependent transcription factors involved in hematopoiesis. cAMP response element binding, CREB phosphorylation and CREB directed transcriptional activity were each increased upon administration of Tat protein. Furthermore, the expression of a second hematopoietic transcription factor, GATA-1, was found to be increased upon Tat administration. As HIV related chemokine receptors are differentially expressed during hematopoietic differentiation, we investigated the effects of Tat protein on the expression of CXCR4 and CCR5, the major coreceptors for HIV-1 infection. Our studies show that megakaryocytopoiesis-associated upregulation of CCR5 and CXCR4 was substantially inhibited by administration of HIV Tat protein. Our studies suggest that Tat protein may contribute hematopoietic dysfunction through a mechanism involving signaling through CBP and CBP-associated transcription factors CREB and GATA-1, and is linked to dysregulation of chemokine receptor expression