Post-transcriptional regulation of the human transforming growth factor-beta 1 gene.

Kim, S.-J.; Park, K.; Koeller, David M.; Kim, Kyung Young; Wakefield, Lalage M.; Sporn, Michael B.; Roberts, Anita B.

doi:10.1016/s0021-9258(18)42270-3

Cited by 152 publications

(7 citation statements)

References 34 publications

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“…Expression of some growth factors are translationally modulated through the binding of cellular proteins to specific sequences in the 5'-UTRs of their mRNAs. The 5'-UTR of transforming growth factor β1 contains a strong stem-loop structure that suppresses translation in adenocarcinomas, but permits translation in pheochromocytomas (43). This portion of the 5'-UTR bound different cytoplasmic proteins in the two cell lines, likely accounting for the differences in translation.…”

Section: Discussionmentioning

confidence: 99%

The 5'-untranslated region of GM-CSF mRNA suppresses translational repression mediated by the 3' adenosine-uridine-rich element and the poly(A) tail

Jarzembowski

Rajagopalan

Shin

et al. 1999

Nucleic Acids Research

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Granulocyte-macrophage colony stimulating factor (GM-CSF) mRNA levels are controlled post-transcriptionally by the 3'-untranslated region (UTR) adenosine-uridine-rich element (ARE). In untransformed, resting cells, the ARE targets GM-CSF mRNA for rapid degradation, thereby significantly suppressing protein expression. We used a rabbit reticulocyte lysate (RRL) cell-free system to examine translational regulation of GM-CSF expression. We uncoupled decay rates from rates of translation by programming the RRL with an excess of mRNAs. Capped, full-length, polyadenyl-ated human GM-CSF mRNA (full-length 5'-UTR AUUUA+A90) and an ARE-modified version (full-length 5'-UTR AUGUA+A90) produced identical amounts of protein. When the 5'-UTR was replaced with an irrelevant synthetic leader sequence (syn 5'-UTR), translation of syn 5'-UTR AUUUA+A90 mRNA was suppressed by >20-fold. Mutation of the ARE or removal of the poly(A) tail relieved this inhibition. Thus, in the absence of a native 5'-UTR, the ARE and poly(A) tail act in concert to block GM-CSF mRNA translation. Substitutions of different regions of the native 5'-UTR revealed that the entire sequence was essential in maintaining the highest rates of translation. However, shorter 10-12 nt contiguous 5'-UTR regions supported 50-60% of maximum translation. The 5'-UTR is highly conserved, suggesting similar regulation in multiple species and in these studies was the dominant element regulating GM-CSF mRNA translation, overriding the inhibitory effects of the ARE and the poly(A) tail.

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Section: Discussionmentioning

confidence: 99%

The 5'-untranslated region of GM-CSF mRNA suppresses translational repression mediated by the 3' adenosine-uridine-rich element and the poly(A) tail

Jarzembowski

Rajagopalan

Shin

et al. 1999

Nucleic Acids Research

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“…Consequently, depletion of hnRNP E1 is sufficient to promote EMT and metastasis of breast epithelial cells (Hussey et al , 2011). TGFβ is a fascinating nexus of post‐transcriptional regulation in that its own translation is also modulated in a cap‐independent fashion through an IRES (Kim et al , 1992; Jenkins et al , 2010). In the future, it would be interesting to assess whether and how the structure of 5′ and 3′UTR regulatory elements change in real time during different steps in cancer development.…”

Section: Introductionmentioning

confidence: 99%

Protein synthesis control in cancer: selectivity and therapeutic targeting

2022

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Translational control of mRNAs is a point of convergence for many oncogenic signals through which cancer cells tune protein expression in tumorigenesis. Cancer cells rely on translational control to appropriately adapt to limited resources while maintaining cell growth and survival, which creates a selective therapeutic window compared to non-transformed cells. In this review, we first discuss how cancer cells modulate the translational machinery to rapidly and selectively synthesize proteins in response to internal oncogenic demands and external factors in the tumor microenvironment. We highlight the clinical potential of compounds that target different translation factors as anti-cancer therapies. Next, we detail how RNA sequence and structural elements interface with the translational machinery and RNA-binding proteins to coordinate the translation of specific pro-survival and pro-growth programs. Finally, we provide an overview of the current and emerging technologies that can be used to illuminate the mechanisms of selective translational control in cancer cells as well as within the microenvironment.

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“…The 2.5 kb TGF-b1 transcript is inherently poorly translated in cultured rat and human cells and in mouse liver, [11][12][13][14] and has unusually long, GC-rich 5 0 and 3 0 untranslated regions (UTR), 15 features that are suggestive of translational control. 16 In contrast to the 3 0 UTR of TGF-b1, which is inherently stimulatory to translation, 17 the 5 0 UTR inhibits translation in vitro.…”

mentioning

confidence: 99%

“…16 In contrast to the 3 0 UTR of TGF-b1, which is inherently stimulatory to translation, 17 the 5 0 UTR inhibits translation in vitro. Deletion analysis of the 5 0 UTR using heterologous reporter gene constructs suggests that the region between nucleotides þ 11 and þ 147, termed the 'D region,' is the key part of this sequence with respect to inhibition of translation 11 (schematically depicted in Figure 1). This region is sufficient to inhibit translation of a reporter gene 22-fold.…”

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confidence: 99%

Y-box protein-1 controls transforming growth factor-β1 translation in proximal tubular cells

Fraser

Phillips

Zhang

et al. 2008

Kidney International

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Transforming growth factor-beta1 (TGF-beta1) mRNA has low basal translational efficiency in proximal tubule cells; however, its translation is stimulated by profibrotic cytokines. We studied the role of the multifunctional Y-box protein-1 (YB-1) in regulating proximal tubule cell TGF-beta1 translation. Using RNA-electrophoretic mobility shift assays and ultraviolet crosslinking, we found two protein complexes of 50 and 100 kDa, which bound to the TGF-beta1 mRNA 5'-untranslated region. Supershift studies using antibodies to YB-1 showed that both sites contained YB-1 as did studies with recombinant YB-1, which demonstrated that it was sufficient to form both complexes. RNA competition experiments confirmed YB-1 binding to the two predicted binding sites; one with high affinity and the other with lower affinity. Strong basal YB-1 association with TGF-beta1 mRNA was found in proximal tubule cells, which decreased when platelet-derived growth factor was used to activate TGF-beta1 translation. In contrast, knockdown of proximal tubule cell YB-1 expression abrogated TGF-beta1 synthesis. Our results suggest that TGF-beta1 translation in proximal tubule cells requires YB-1 binding to a high-affinity site in the 5'-untranslated region of its mRNA; however, binding to a low-affinity site inhibits basal translation.

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Post-transcriptional regulation of the human transforming growth factor-beta 1 gene.

Cited by 152 publications

References 34 publications

The 5'-untranslated region of GM-CSF mRNA suppresses translational repression mediated by the 3' adenosine-uridine-rich element and the poly(A) tail

The 5'-untranslated region of GM-CSF mRNA suppresses translational repression mediated by the 3' adenosine-uridine-rich element and the poly(A) tail

Protein synthesis control in cancer: selectivity and therapeutic targeting

Y-box protein-1 controls transforming growth factor-β1 translation in proximal tubular cells

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