Mammalian ribonucleotide reductase R1 mRNA stability under normal and phorbol ester stimulating conditions: involvement of a cis-trans interaction at the 3′ untranslated region.

Chen, F.Y.; Amara, Francis M.; Wright, Jim A.

doi:10.1002/j.1460-2075.1993.tb06075.x

Cited by 65 publications

(66 citation statements)

References 34 publications

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“…Interestingly, in one of the original descriptions of PTEN, it was identified as a TGF-b regulated gene (Li and Sun, 1997). RRM1 has an element in the 3 0 -untranslated region that appears to be involved in message stability, and it is responsive to TGF-b (Chen et al, 1993;Amara et al, 1996). It is thus conceivable that the increased levels of RRM1 in H23-R1 cells result in increased availability of a factor that is involved in the regulation of PTEN message.…”

Section: Discussionmentioning

confidence: 99%

RRM1-induced metastasis suppression through PTEN-regulated pathways

2003

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Lung cancer is the leading cause of cancer-related mortality in the United States. Only 15% of patients with this disease survive 5 years or longer. Early metastatic spread is the single most important reason for this poor outcome. The survival of patients with pathological stage I disease, that is, no evidence for metastatic spread, and molecular aberrations on chromosome 11p15.5 is equal to that of patients with stage II disease, that is, metastatic spread to hilar lymph nodes. RRM1 is a gene in this region, and it is haploinsufficient in at least 34% stage I patients. Here, we show that overexpression of RRM1 in human and mouse lung cancer cell lines induced PTEN expression, reduced phosphorylation of focal adhesion kinase (FAK), suppressed migration, invasion, and metastasis formation, and increased survival in an animal model. Increased PTEN expression was required for the RRM1-induced suppression of cell motility and FAK phosphorylation. We conclude that RRM1 functions as a metastasis suppressor gene through induction of PTEN expression.

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Section: Discussionmentioning

confidence: 99%

RRM1-induced metastasis suppression through PTEN-regulated pathways

2003

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“…Akashi et al (2) reported that stabilization of GM-CSF mRNA by PKC activation is mediated by AU-rich sequences. Recently, Chen et al (16) identified a region in the 3'UTR of ribonucleotide reductase R1 mRNA and a protein of 52 to 57 kDa interacting with this region that are involved in TPA-induced stabilization. Stabilization after TPA treatment has also been reported for collagenase (12), interleukin 1 (22), GAP-43 (53), GLUT1 (61), and TGFP1 (65) mRNAs.…”

Section: Discussionmentioning

confidence: 99%

Multiple instability-regulating sites in the 3' untranslated region of the urokinase-type plasminogen activator mRNA.

Nanbu¹,

Menoud²,

Nagamine³

1994

Mol. Cell. Biol.

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In LLC-PK, cells urokinase-type plasminogen activator (uPA) mRNA has a short half-life. It is stabilized by inhibition of protein synthesis and by downregulation of protein kinase C (PKC). In the present study on uPA mRNA metabolism, we focused our attention on the 3' untranslated region (3'UTR) of the uPA mRNA, as this region is long and highly conserved among several mammalian species, including mice and humans. To investigate the possible role of the 3'UTR of uPA mRNA in mRNA metabolism, we inserted this region into the 3'UTR of the rabbit P-globin gene that is linked to the cytomegalovirus promoter and stably transfected it into LLC-PK1 cells. While the parental globin mRNA was stable, the chimeric mRNA was degraded as rapidly as endogenous uPA mRNA, suggesting that the 3'UTR of uPA mRNA contains most of the information required for its rapid turnover. Further analysis showed that there are at least three independent determinants of instability in the 3'UTR; one is an AU-rich sequence located immediately 3' of the poly(A) addition signal, and one is a sequence containing a stem structure. One determinant seems to require ongoing RNA synthesis for its activity. All chimeric unstable globin mRNAs became stable in the presence of cycloheximide, a protein synthesis inhibitor, suggesting that the stabilization of mRNA by protein synthesis inhibition is not through a specific sequence in the mRNA. In PKC-downregulated cells, globin mRNAs with the complete 3'UTR or the AU-rich sequence were stabilized, suggesting that PKC downregulation stabilizes uPA mRNA through the AU-rich sequence. Here we discuss the significance of multiple, independently acting instability determinants in the regulation of uPA mRNA metabolism.

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“…This was reported to be the result of mRNA stabilization caused by protein binding to a specific regulatory 49-nucleotide element in the 3Ј-UTR of the mRNA. However, no studies on cell cycle-regulated R1 gene expression were reported (13). To study mRNA stabilization as a mechanism for regulating the R1 mRNA levels during the cell cycle, we introduced the putative regulatory 49-mer from the R1 gene into the luciferase reporter gene.…”

Section: Transcriptional Regulation Of the R1 Promoter During Thementioning

confidence: 99%

Two YY-1-binding Proximal Elements Regulate the Promoter Strength of the TATA-less Mouse Ribonucleotide Reductase R1 Gene

Johansson

Hjortsberg

Thelander

1998

Journal of Biological Chemistry

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Ribonucleotide reductase is essential for DNA synthesis. In mammalian cells, the enzyme consists of two nonidentical subunits, proteins R1 and R2. The expression of the mouse R1 and R2 genes is strictly correlated to S phase. Using promoter-reporter gene constructs, we have defined a region of the TATA-less mouse ribonucleotide reductase R1 gene promoter that correlates reporter gene expression to S phase. This is demonstrated in stably transformed cells both synchronized by serum starvation and separated by centrifugal elutriation, suggesting that the R1 gene expression during the cell cycle is mainly regulated at the transcriptional level. The region contains four protein-binding DNA elements, ␤ (nucleotides ؊189 to ؊167), ␣ (؊98 to ؊76), Inr (؊4 to ؉16), and ␥ (؉34 to ؉61), together regulating promoter activity. The nearly identical upstream elements, ␣ and ␤, each form three DNA-protein complexes in gel shift assays. We have identified YY1 as a component in at least one of the complexes using supershift antibodies and a yeast one-hybrid screening of a mouse cDNA library using the ␣ element as a target. Transient transfection assays demonstrate that the ␣ and ␤ elements are mainly important for the R1 promoter strength and suggest that YY1 functions as an activator.The enzyme ribonucleotide reductase is essential for de novo synthesis of deoxyribonucleotides. In this perspective, ribonucleotide reductase plays a central role in providing the precursors for DNA synthesis. Mammalian ribonucleotide reductase consists of two non-identical homodimeric subunits, proteins R1 and R2 (1). Protein R1 (large subunit) contains the active site and allosteric sites for regulating enzyme activity. Protein R2 (small subunit) carries a tyrosyl free radical essential for enzyme activity. In quiescent or differentiated cells, none of the two subunits can be detected. In proliferating cells, the expression of protein R2 is S phase specific, whereas protein R1 shows a constant level throughout the cell cycle (2-4). However, both the R1 and R2 mRNA levels vary in parallel during the cell cycle with negligible levels during G 0 /G 1 and maximal levels during S phase (5, 6). The R1 and R2 promoters are also activated in resting cells upon UV irradiation leading to nucleotide excision repair (7).Genomic clones covering the mouse R1 and R2 genes have been isolated (8, 9). The R2 promoter contains a TATA-box and a proximal element, called ␣, that contains an NF-Y binding CCAAT motif (10).The R1 gene consists of 19 exons that covers 26 kb. 1 In contrast to the R2 promoter, the R1 promoter is TATA-less. DNase I footprinting assays proximal to the transcription start revealed two protected regions, ␣ (nt Ϫ98 to Ϫ76) and ␤ (nt Ϫ189 to Ϫ167) (8). These two regions are each 23 nt and identical except for one nucleotide. Three DNA-protein complexes, A, B, and C, are formed when oligonucleotides corresponding to the ␣ or ␤ footprints are used in gel shift assays. Complexes A and B are present at constant levels during the cell cycle, whereas c...

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Mammalian ribonucleotide reductase R1 mRNA stability under normal and phorbol ester stimulating conditions: involvement of a cis-trans interaction at the 3′ untranslated region.

Cited by 65 publications

References 34 publications

RRM1-induced metastasis suppression through PTEN-regulated pathways

RRM1-induced metastasis suppression through PTEN-regulated pathways

Multiple instability-regulating sites in the 3' untranslated region of the urokinase-type plasminogen activator mRNA.

Two YY-1-binding Proximal Elements Regulate the Promoter Strength of the TATA-less Mouse Ribonucleotide Reductase R1 Gene

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