Comparative expression of tristetraprolin (TTP) family member transcripts in normal human tissues and cancer cell lines
The Office of Clinical Research, National Institute of Environmental Health Sciences, NIEHS MD A2-05, 111 Alexander Drive, Research Triangle Park, NC 27709, USA. Archives of Biochemistry and Biophysics
(Impact Factor: 3.02).
07/2007; 462(2):278-85. DOI: 10.1016/j.abb.2007.04.011
The tristetraprolin (TTP) family of tandem zinc finger proteins comprises three members in man and most other mammals, with a fourth expressed in rodents. In mice, gene disruption of TTP itself leads to a systemic inflammatory syndrome that is mediated in large part by over-expression of tumor necrosis factor alpha (TNF). This increased expression is secondary to stabilization of the TNF mRNA in the TTP KO mice, a finding that led to the characterization of TTP as an mRNA binding protein that can promote the removal of the poly(A) tail from selected mRNAs and facilitate their nucleolytic destruction. The other human family members behave similarly to TTP in over-expression studies of transfected cells, but gene disruption experiments have implicated them in different physiological processes. In the present study, we developed a real-time PCR assay for all three human family members that allowed for comparative measurements of all three family members in the same tissues and cells. We used this assay to quantitate expression levels of all three transcripts in a variety of normal human tissues, as well as in the ;;NCI 60", a well characterized panel of human tumor cell lines. Although studies in fibroblasts and macrophages derived from knockout mice have failed to demonstrate compensatory expression of the family members in terms of transcript levels, it remains possible that the different family members can function as ;;TTP equivalents" in certain physiological or pathological circumstances.
Available from: Gerald M Wilson
- "Since proliferation of this tumor cell line is driven by an IL-3 autocrine loop, suppression of IL-3 synthesis by TTP dramatically slowed cell growth and significantly delayed tumor formation in murine xenografts. More recently, surveys of TTP expression in human tumors and cancer cell lines have yielded several findings suggesting that TTP may function as a tumor suppressor in diverse neoplastic contexts (Brennan et al., 2009; Carrick and Blackshear, 2008). First, TTP expression was suppressed in many human cancers and cultured cancer cell lines relative to non-transformed tissues from many tissue sources. "
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ABSTRACT: Cancer and senescence are both complex transformative processes that dramatically alter many features of cell physiology and their interactions with surrounding tissues. Developing the wide range of cellular features characteristic of these conditions requires profound alterations in global gene expression patterns, which can be achieved by suppressing, activating, or uncoupling cellular gene regulatory pathways. Many genes associated with the initiation and development of tumors are regulated at the level of mRNA decay, frequently through the activity of AU-rich mRNA-destabilizing elements (AREs) located in their 3'-untranslated regions. As such, cellular factors that recognize and control the decay of ARE-containing mRNAs can influence tumorigenic or senescent phenotypes mediated by products of these transcripts. In this review, we discuss evidence showing how suppressed expression and/or activity of the ARE-binding protein tristetraprolin (TTP) can contribute to these processes. Next, we outline current findings linking TTP suppression to exacerbation of individual tumorigenic phenotypes, and the roles of specific TTP substrate mRNAs in mediating these effects. Finally, we survey potential mechanisms that cells may employ to suppress TTP expression in cancer, and propose potential diagnostic and therapeutic strategies that may exploit the relationship between TTP expression and tumor progression or senescence.
Available from: Dan A Dixon
- "Interestingly, an AU-rich region has been identified within the 3'UTR of HPV16
E6/E7 RNA that can mediate rapid decay . The results
presented here (Figure 8) and that of others  demonstrate TTP
to be abundantly expressed in normal uterine cervix. Based on these
observations, it is plausible that that TTP may play a protective role in the
early stages of HPV infection by targeting E6/E7 RNA for rapid degradation. "
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ABSTRACT: The RNA-binding protein tristetraprolin (TTP) regulates expression of many cancer-associated and proinflammatory factors through binding AU-rich elements (ARE) in the 3'-untranslated region (3'UTR) and facilitating rapid mRNA decay. Here we report on the ability of TTP to act in an anti-proliferative capacity in HPV18-positive HeLa cells by inducing senescence. HeLa cells maintain a dormant p53 pathway and elevated telomerase activity resulting from HPV-mediated transformation, whereas TTP expression counteracted this effect by stabilizing p53 protein and inhibiting hTERT expression. Presence of TTP did not alter E6 and E7 viral mRNA levels indicating that these are not TTP targets. It was found that TTP promoted rapid mRNA decay of the cellular ubiquitin ligase E6-associated protein (E6-AP). RNA-binding studies demonstrated TTP and E6-AP mRNA interaction and deletion of the E6-AP mRNA ARE-containing 3'UTR imparts resistance to TTP-mediated downregulation. Similar results were obtained with high-risk HPV16-positive cells that employ the E6-AP pathway to control p53 and hTERT levels. Furthermore, loss of TTP expression was consistently observed in cervical cancer tissue compared to normal tissue. These findings demonstrate the ability of TTP to act as a tumor suppressor by inhibiting the E6-AP pathway and indicate TTP loss to be a critical event during HPV-mediated carcinogenesis.
Available from: usda.gov
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ABSTRACT: Inflammatory diseases place a heavy burden on the American health care system. Tristetraprolin, a zinc-dependent mRNA binding protein decreases the stability of mRNAS coding for some proinflammatory cytokines. Tristetraprolin-deficient mice develop a profound inflammatory syndrome. Tristetraprolin is a potential cancer therapy due to its control of vascular endothelial growth factor mRNA stability. Cinnamon extract stimulates the expression of antiinflammatory tristetraprolin. Bioactive compound(s) in cinnamon extract define its molecular mechanisms. Cinnamon is potentially important in tristetraprolin-mediated inflammatory diseases.
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