Adaptive and maladaptive expression of the Mrna regulatory protein HuR

Abstract

The RNA-binding proteins involved in regulation of mRNA post-transcriptional processing and translation control the fates of thousands of mRNA transcripts and basic cellular processes. The best studied of these, HuR, is well characterized as a mediator of mRNA stability and translation, and more recently, as a factor in nuclear functions such as pre-mRNA splicing. Due to HuR's role in regulating thousands of mRNA transcripts, including those for other RNA-binding proteins, HuR can act as a master regulator of cell survival and proliferation. HuR itself is subject to multiple post-translational modifications including regulation of its nucleocytoplasmic distribution. However, the mechanisms that govern HuR levels in the cell have only recently begun to be defined. These mechanisms are critical to cell health, as it has become clear in recent years that aberrant expression of HuR can lead alternately to decreased cell viability or to promotion of pathological proliferation and invasiveness. HuR is expressed as alternate mRNAs that vary in their untranslated regions, leading to differences in transcript stability and translatability. Multiple transcription factors and modulators of mRNA stability that regulate HuR mRNA expression have been identified. In addition, translation of HuR is regulated by numerous microRNAs, several of which have been demonstrated to have anti-tumor properties due to their suppression of HuR expression. This review summarizes the current state of knowledge of the factors that regulate HuR expression, along with the circumstances under which these factors contribute to cancer and inflammation.

Krüppel -Like Factor 8 is a Stress-Responsive Transcription Factor that Regulates Expression of HuR

“…A moderate level of HuR expression is required for cell survival, since its absence results in cell death [55]. Yet, its overexpression is well-established to play a role in oncogenic transformation and tumor invasiveness [11, 12, 22, 29, 45, 56-64]. Therefore, even under conditions of cell stress, when normal translational regulation may be impaired, it is critical that HuR expression is maintained at appropriate levels.…”

“…Because HuR function must be finely tuned to create a balance between cell proliferation and survival on one hand, and oncogenic transformation on the other, its expression is tightly controlled at multiple levels [12]. At a post-transcriptional level, HuR mRNA levels are controlled by multiple regulators of mRNA stability [13, 14], including HuR itself, since its expression may be autoregulated [15, 16].…”

Effects of HuR downregulation on anaplastic thyroid cancer cells

“…HuR is located into the nucleus and, in response to stimuli, can shuttle to the cytoplasm to allow its mRNA target to be processed. Several studies demonstrated that HuR is overexpressed and delocalized in the cytoplasm in numerous cancers, including breast cancer, lung adenocarcinoma, ovarian cancer, laryngeal squamous cell cancer and colon cancer (6,7). Moreover, various mRNA of tumorigenesis factors, oncogenes and anti-apoptotic factors have been identified as HuR targets (5).…”

Induction of VEGFA mRNA translation by CoCl2 mediated by HuR

“…14 HuR, in particular, can regulate hundreds of target transcripts and is considered to be a key regulator of many cellular functions, including proliferation, cellular stress response, and cell survival. 15 Indeed, HuR promotes the expression of general stress-response proteins (HSP70, HO-1, SOD1, p62) and hypoxia-response proteins, including HIF-1a and VEGFA. [16][17][18][19][20] Through its influence on subsets of cellular proteins, HuR has been linked to various pathologies, including inflammatory diseases and cancer.…”