Tristetraprolin: Roles in cancer and senescence

doi:10.1016/j.arr.2012.02.005

Ageing Research Reviews

Volume 11, Issue 4, September 2012, Pages 473-484

https://doi.org/10.1016/j.arr.2012.02.005 Get rights and content

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.

Highlights

► Tristetraprolin (TTP) binds mRNAs containing AU-rich elements (AREs) and targets them for rapid mRNA decay. ► TTP expression and/or activity are potently downregulated in many human cancers, particularly advanced and aggressive cancers. ► TTP suppresses the expression of many mRNAs encoding factors that control diverse aspects of tumor development and senescence; as such, loss of TTP in cancer reprograms a gene regulatory network that exacerbates many tumorigenic phenotypes.

Section snippets

The diverse cellular features of cancer

Decades of research have defined cancer as a disease caused by dynamic changes in the genome. Mutations acquired familially or accumulated over time can activate oncogenes through dominant gain of function and disable tumor suppressor genes by recessive loss of function (Hanahan and Weinberg, 2011). The unstable genome of a tumor cell not only makes cancer unique to each patient, but also provides a mechanism by which a single tumor can be heterogeneous in composition. This pathological

Post-transcriptional gene regulation and tristetraprolin

In eukaryotic cells, gene expression is normally tightly regulated through multiple control mechanisms. These regulatory systems are essential to ensure that gene products, whether they be protein or RNA, are maintained within levels appropriate for cellular growth, maintenance, function and apoptosis. An important determinant governing protein synthetic rates is the cytoplasmic concentration of their corresponding mRNAs, which is dependent on rates of both mRNA synthesis and degradation. The

Cancer-related inflammation

The role of inflammation during normal homeostasis is to protect the body against pathogens, injury, and in some cases tumors. However, the functions carried out by inflammatory cells and factors can also benefit tumor progression. The long term abuse of inflammatory mechanisms can alter gene expression patterns in cells, resulting in changes in cellular phenotypes that lead to dysplasia and cancer. Approximately 25% of all human cancers are attributed to the effects of chronic infections that

Senescence

Senescence is a mechanism employed to prevent cell growth past a certain number of replicative cycles, known as the Hayflick's limit (Lyden et al., 2001). This constraint varies depending on cell type but is normally about 40 to 60 replications based on critical telomere length. Morphological and biochemical alterations of senescent cells include flattening of cytoplasm and increased granularity, induction of β-galactosidase and alterations in gene expression patterns (Holopainen et al., 2011).

Oncogenic mechanisms that suppress tristetraprolin

Several studies have shown that TTP expression is suppressed in many cancers, and that there is frequently an inverse correlation between TTP levels and tumor aggressiveness. Following from these findings, numerous groups have examined the mechanisms linking loss of TTP expression to tumor development, from perspectives of both global cellular phenotypes and also characterization of deregulated TTP substrate mRNAs (described above). However, among the fundamental questions that remain

Future directions

Owing to the complex and varied cellular mechanisms responsible for initiation and development of cancers, disease presentation, optimal treatment strategies, and prognosis can vary widely between patients. While activation of specific oncogenes is a common theme, their effects on intracellular signaling pathways or specific gene expression events ultimately direct dramatic reprogramming of gene regulatory networks in transformed cells. This oncogenic “amplification response” provides a means

Acknowledgements

Research in the Wilson lab contributing to this manuscript was funded by NIH R01 CA102428 and a Research Scholar Grant from the American Cancer Society (to G.M.W.). C.R.R. is supported in part by NIH T32 GM066706. We also apologize to all of our colleagues whose excellent work could not be cited owing to space limitations.

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The proliferation effect of TTP depends on its ability to bind to ARE sequences in the mRNA of cell cycle regulators such as c-Myc and cyclin D1 [126]. c-Myc is a transcription factor that regulates around 15% of the human transcriptome [127] including several genes involved in cell proliferation and tumor development [1]. TTP has been shown to regulate the stability of the c-Myc transcript in hepatocellular carcinoma cell lines, malignant gliomas [126], lymphoma [44] and breast cancer cells [113,128].
Tristetraprolin (TTP) is a nucleocytoplasmic 326 amino acid protein whose sequence is characterized by possessing two CCCH-type zinc finger domains. In the cytoplasm TTP function is to promote the degradation of mRNAs that contain adenylate/uridylate–rich elements (AREs). Mechanistically, TTP promotes the recruitment of poly(A)-specific deadenylases and exoribonucleases. By reducing the half-life of about 10% of all the transcripts in the cell TTP has been shown to participate in multiple cell processes that include regulation of gene expression, cell proliferation, metabolic homeostasis and control of inflammation and immune responses. However, beyond its role in mRNA decay, in the cell nucleus TTP acts as a transcriptional coregulator by interacting with chromatin modifying enzymes. TTP has been shown to repress the transactivation of NF-κB and estrogen receptor suggesting the possibility that it participates in the transcriptional regulation of hundreds of genes in human cells and its possible involvement in breast cancer progression. In this review, we discuss the cytoplasmic and nuclear functions of TTP and the effect of the dysregulation of its protein levels in the development of human diseases. We suggest that TTP be classified as a moonlighting tumor supressor protein that regulates gene expression through two different mechanims; the decay of ARE-mRNAs and a transcriptional coregulatory function.
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Tristetraprolin (TTP) is the most well-known member of RNA-binding zinc-finger protein that play a significant role in accelerating mRNA decay. Increasingly studies have reported that TTP was functioned as a tumor suppressor gene in several types of carcinomas, while its underlying mechanism is not clear yet. In the current study, we found that TTP overexpression decreased cell proliferation and increased cell death in lung adenocarcinoma cells, with the cell cycle arrest at the S phase. Remarkably, instead of inducing cell apoptosis directly, TTP overexpression alters cell autophagy. Our studies demonstrate that TTP overexpression has no effect on apoptosis related genes, but decreases the expression of autophagy-related genes, including Beclin 1 and LC3II. The level of autophagy flux assessed by infection with the mGFP–RFP–LC3 adenovirus construction has been blocked by TTP overexpression. Moreover, the autophagic vacuoles number detected by transmission electron microscopy decreased with TTP expression up-regulation. Our results indicate, for the first time, that TTP suppresses cell proliferation and increases cell death through cell autophagy pathway in lung cancer cells. Our study provides a new angle of view for TTP function as a tumor suppressor which could be targeted in tumor treatment.
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ReviewTristetraprolin: Roles in cancer and senescence

Abstract

Highlights

Section snippets

The diverse cellular features of cancer

Post-transcriptional gene regulation and tristetraprolin

Cancer-related inflammation

Senescence

Oncogenic mechanisms that suppress tristetraprolin

Future directions

Acknowledgements

Biochem. Pharmacol.

Cell

Cell

Cancer Cell

Cell

J. Biol. Chem.

Cancer Cell

Mol. Cell

Cancer Cell

Gene

Cell

Cell

Cell

Cell. Signal.

Int. Rev. Cell Mol. Biol.

J. Biol. Chem.

Exp. Cell Res.

J. Biol. Chem.

Cell

J. Biol. Chem.

The RNA-binding zinc-finger protein tristetraprolin regulates AU-rich mRNAs involved in breast cancer-related processes

Oncogene

Post-transcriptional regulation of proinflammatory proteins

J. Leukoc. Biol.

Integrins in angiogenesis and lymphangiogenesis

Nat. Rev. Cancer

A review of the latest clinical compounds to inhibit VEGF in pathological angiogenesis

Expert. Opin. Ther. Targets

AU-rich elements and associated factors: are there unifying principles?

Nucleic Acids Res.

Constitutive ERK activity induces downregulation of tristetraprolin, a major protein controlling interleukin8/CXCL8 mRNA stability in melanoma cells

Am. J. Physiol. Cell Physiol.

The mRNA-destabilizing protein tristetraprolin is suppressed in many cancers, altering tumorigenic phenotypes and patient prognosis

Cancer Res.

RNA sequence elements required for high affinity binding by the zinc finger domain of tristetraprolin: Conformational changes coupled to the bipartite nature of AU-rich mRNA-destabilizing motifs

J. Biol. Chem.

The role of mRNA turnover in the regulation of tristetraprolin expression: evidence for an extracellular signal-regulated kinase-specific, AU-rich element-dependent, autoregulatory pathway

J. Immunol.

MicroRNA signatures in human cancers

Nat. Rev. Cancer

Feedback inhibition of macrophage tumor necrosis factor-α production by tristetraprolin

Science

Tristetraprolin downregulates the expression of both VEGF and COX-2 in human colon cancer

Hepatogastroenterology

Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability

Carcinogenesis

Oncogenes and cancer

N. Engl. J. Med.

Stimulation of methotrexate resistance and dihydrofolate reductase gene amplification by c-myc

Oncogene

Cytokines in cancer pathogenesis and cancer therapy

Nat. Rev. Cancer

Tristetraprolin inhibits Ras-dependent tumor vascularization by inducing vascular endothelial growth factor mRNA degradation

Mol. Biol. Cell

A matter of life and cell death

Science

Review
Tristetraprolin: Roles in cancer and senescence