CREB/ATF-Dependent Repression of Cyclin A by Human T-Cell Leukemia Virus Type 1 Tax Protein

Abstract

Expression of the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein Tax is correlated with cellular transformation contributing to the development of adult T-cell leukemia. Tax has been shown to modulate the activities of several cellular promoters. Existing evidence suggests that Tax need not directly bind to DNA to accomplish these effects but rather that it can act through binding to cellular factors, including members of the CREB/ATF family. Exact mechanisms of HTLV-1 transformation of cells have yet to be fully defined, but the process is likely to include both activation of cellular-growth-promoting factors and repression of cellular tumor-suppressing functions. While transcriptional activation has been well studied, transcriptional repression by Tax, reported recently from several studies, remains less well understood. Here, we show that Tax represses the TATA-less cyclin A promoter. Repression of the cyclin A promoter was seen in both ts13 adherent cells and Jurkat T lymphocytes. Two other TATA-less promoters, cyclin D3 and DNA polymerase ␣, were also found to be repressed by Tax. Interestingly, all three promoters share a common feature of at least one conserved upstream CREB/ATF binding site. In electrophoretic mobility shift assays, we observed that Tax altered the formation of a complex(es) at the cyclin A promoter-derived ATF site. Functionally, we correlated removal of the CREB/ATF site from the promoter with loss of repression by Tax. Furthermore, since a Tax mutant protein which binds CREB repressed the cyclin A promoter while another mutant protein which does not bind CREB did not, we propose that this Tax repression occurs through protein-protein contact with CREB/ATF.Infection with human T-cell leukemia virus type 1 (HTLV-1) has been linked to the development of several diseases: adult T-cell leukemia (ATL), tropical spastic paraparesis, and various neurological disorders termed HTLV-1-associated myelopathy (33). The HTLV-1-encoded oncoprotein Tax has been implicated in the transformation of T cells (reviewed in reference 91), as well as in tumor formation in transgenic mice (26). Although the precise mechanisms utilized by Tax to induce transformation are not known, this protein has been shown to modulate cellular genes that are involved in cellular proliferation and cell cycle control (reviewed in reference 55). Tax up-regulates expression of interleukin-2 (IL-2), IL-2 receptor, c-fos, c-Jun, erg-1, and granulocyte-macrophage colony-stimulating factor (reviewed in references 32 and 51; 52) and represses expression of the ␤-polymerase, c-myb, Lck, and p53 promoters (11,39,48,57,84). Tax has also been shown to affect the functions of IKK␥ (10, 27, 40), c-myc (69), Bax (8), MAD1 (41), cyclin D (56), and MyoD (63).Cyclins are critical factors in cell cycle progression (25,71,72). Cyclins associate with cyclin-dependent kinases and regulate the functions of cellular proteins that are required for progression through the cell cycle (G 1 , S, G 2 , and M) phases. The D cyclins are induced by ...

Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion

“…Although ATF-1 and cJun are generally considered as transcription activators, ATF-1 can also repress transcription (Dong et al, 2002). ATF/ CREB mediate repression of cyclin A promoter by human T-cell leukemia virus protein Tax (Kibler and Jeang, 2001). Crosstalk between AP-1 family members and p53 is well documented, which may involve sequestering of the co-activator p300/CBP (Shaulian and Karin, 2002;Sun et al, 2004).…”

BCL3 Acts as a Negative Regulator of Transcription from the Human T-cell Leukemia Virus Type 1 Long Terminal Repeat through Interactions with TORC3

“…In this manner, Tax-mediated up-regulation of BCL3 may mediate trans-suppression of several genes, such as those encoding DNA polymerase ␤, c-Myb, or cyclin A (31)(32)(33).…”

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

“…Thus, by increasing p21 waf1 , one would predict that Tax facilitates increased G 1 progression and initiates G 1 /S arrest. However, since Tax also appears to repress cyclin A expression (Kibler and Jeang, 2001), the balance is tipped in favor of cyclin D/cdk4/6Cdk2 complexes (Kehn et al, 2004) and cell cycle progression is promoted. Therefore, the ability of Tax to increase p21 waf1 expression may explain why Tax-expressing cells accelerate through G 1 and fail to engage the G 1 /S checkpoint.…”

“…While extensive study of chromosomal abnormalities in ATL patients and in HTLV-I infected/transformed cells has demonstrated a wide variety of clonal chromosomal abnormalities with complicated karyotypes in both numbers and structures, no specific karyotypic abnormalities have been associated with ATL cells (Sandberg, 1980;Kibler and Jeang, 2001). Although chromosomal abnormalities appear to be random in ATL cells, certain types of aberrations, including duplications, deletions, translocations, rearrangements and aneuploidy, are commonly observed in these cells and it remains possible that specific chromosomal alterations may be responsible for the development of ATL.…”

“…Repression of cyclin A expression by Tax may remove this regulatory mechanism and allow redundant DNA replication, which could contribute to the aneuploidy often observed in HTLV-I-infected cells (Kibler and Jeang, 2001). Since cyclin A also functions to regulate cell exit from mitosis (Walker and Maller, 1991), Taxmediated repression of cyclin A may accelerate mitosis and contribute to failed mitotic checkpoint activation (Kibler and Jeang, 2001). While the rise in mitotic cyclins (cyclin B and its partner, Cdk1) during S phase are required for entry into mitosis (Liu et al, 2005), the activities of mitotic cyclins are held in check until completion of S and G 2 phases.…”