p73 expression is regulated by RNPC1, a target of the p53 family, via mRNA stability.
01 Jul 2012-Molecular and Cellular Biology (American Society for Microbiology)-Vol. 32, Iss: 13, pp 2336-2348
TL;DR: The mutual regulation between p73 and RNPC1 constitutes a novel feed-forward loop, which might be explored as a target for tumors without a functional p53.
Abstract: p73, a p53 family tumor suppressor, is expressed as TA and ΔN isoforms. Due to the role of p73 in tumor suppression and neural development, its expression and activity are tightly regulated by multiple mechanisms, including transcription and posttranslational modifications. Here, we found that p73 mRNA stability is regulated by RNPC1, an RNA binding protein and a target of the p53 family. We also showed that a CU-rich element in the 3′ untranslated region of p73 is recognized by and responsive to RNPC1. To explore the physiological significance of RNPC1-regulated p73 expression, we showed that the loss of RNPC1 in p53-null mouse embryonic fibroblasts leads to reduced expression of p73, along with decreased expression of p21, p130, and γ-H2A.X, and consequently a decreased number of senescent cells. Furthermore, we observed that knockdown of TAp73 or p21, another target of RNPC1, attenuates the inhibitory effect of RNPC1 on cell proliferation and premature senescence, whereas combined knockdown of TAp73 and p21 completely abolishes it. Due to the fact that RNPC1 is a target of p73, the mutual regulation between p73 and RNPC1 constitutes a novel feed-forward loop, which might be explored as a target for tumors without a functional p53.
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TL;DR: A new PTEN regulating mechanism was revealed that PTEN was positively regulated by R BM38 via stabilizing its transcript stability, which in turn alleviated RBM38-mediated growth suppression.
Abstract: PTEN (phosphatase and tensin homolog gene on chromosome 10), a well-characterized tumor suppressor, is a key regulator of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway involved in cell survival, metastasis and cell renewal. PTEN expression is closely related to the phenotype, prognosis and drug selection in breast cancer. It is mainly regulated by transcriptional and post-transcriptional modifications. RNA binding motif protein 38 (RBM38), an RNA-binding protein (RBP) and a target of P53 family, plays a crucial role in the regulation of cellular processing, especially in post-transcription regulation and gene transcription. In this study, we investigated a new post-transcription regulation mechanism of PTEN expression by RBM38 in breast cancer. Immunohistochemistry, lentivirus transfections, Western blotting analysis, qRT-PCR and ELISA were used to conduct the relation between RBM38 and PTEN. RNA immunoprecipitation, RNA electrophoretic mobility shift and dual-luciferase reporter assays were employed to identify the direct binding sites of RBM38 with PTEN transcript. Colony formation assay was conducted to confirm the function of PTEN in RBM38-induced growth suppression. PTEN expression was positively associated with the expression of RBM38 in breast cancer tissues and breast cancer cells. Moreover, RBM38 stabilized PTEN transcript to enhance PTEN expression via binding to multiple AU/U- rich elements (AREs) in 3′-untranslated region (3′-UTR) of PTEN transcript. Additionally, specific inhibitors of PTEN activity and small interfering (siRNA) of PTEN expression inhibited RBM38-mediated suppression of proliferation, which implied that RBM38 acted as a tumor suppressor partly by enhancing PTEN expression. The present study revealed a new PTEN regulating mechanism that PTEN was positively regulated by RBM38 via stabilizing its transcript stability, which in turn alleviated RBM38-mediated growth suppression.
90 citations
TL;DR: Data support targeting HDACs and KDM1A in combination as a strategy for GBM and identifies TP53 and TP73 as being altered in response to treatment.
Abstract: Background Glioblastoma (GBM) is the most common and aggressive form of brain cancer. Our previous studies demonstrated that combined inhibition of HDAC and KDM1A increases apoptotic cell death in vitro. However, whether this combination also increases death of the glioma stem cell (GSC) population or has an effect in vivo is yet to be determined. Therefore, we evaluated the translational potential of combined HDAC and KDM1A inhibition on patient-derived GSCs and xenograft GBM mouse models. We also investigated the changes in transcriptional programing induced by the combination in an effort to understand the induced molecular mechanisms of GBM cell death. Methods Patient-derived GSCs were treated with the combination of vorinostat, a pan-HDAC inhibitor, and tranylcypromine, a KDM1A inhibitor, and viability was measured. To characterize transcriptional profiles associated with cell death, we used RNA-Seq and validated gene changes by RT-qPCR and protein expression via Western blot. Apoptosis was measured using DNA fragmentation assays. Orthotopic xenograft studies were conducted to evaluate the effects of the combination on tumorigenesis and to validate gene changes in vivo. Results The combination of vorinostat and tranylcypromine reduced GSC viability and displayed efficacy in the U87 xenograft model. Additionally, the combination led to changes in apoptosis-related genes, particularly TP53 and TP73 in vitro and in vivo. Conclusions These data support targeting HDACs and KDM1A in combination as a strategy for GBM and identifies TP53 and TP73 as being altered in response to treatment.
62 citations
Additional excerpts
...Several studies link p53 and p73; p53 directly regulates p73 at the transcriptional level(40,41) as well as indirectly by influencing p73 RNA stability.(42) To investigate the specific role of p53 in the regulation of TAp73, we transfected p53-null GBM cells with wild-type p53 and measured changes in TAp73 mRNA expression after each treatment (Fig....
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TL;DR: The results suggest that Rbm38 is necessary for normal hematopoiesis and for suppressing accelerated aging and tumorigenesis and the p53-Rbm38 axis might be explored for extending longevity and for tumor suppression.
Abstract: RNA-binding motif protein 38 (Rbm38), also called RNPC1 [RNA-binding region (RNP1, RRM) containing 1], is a target of the p53 family and modulates p53 expression via mRNA translation. To investigate the biological function of Rbm38 in vivo, we generated an Rbm38-null mouse model. We showed that mice deficient in Rbm38 exhibit signs of accelerated aging and are prone to hematopoietic defects and spontaneous tumors. To determine the biological significance of the p53-Rbm38 loop, we showed that Rbm38 deficiency enhances accumulation of p53 induced by ionizing radiation (IR) and sensitizes mice to IR-induced lethality in a p53-dependent manner. Most importantly, Rbm38 deficiency markedly decreases the tumor penetrance in mice heterozygous for p53 via enhanced p53 expression. Interestingly, we found that Rbm38 deficiency shortens the life span of, and promotes lymphomagenesis in, mice deficient in p53. These results provide genetic evidence that Rbm38 is necessary for normal hematopoiesis and for suppressing accelerated aging and tumorigenesis. Thus, the p53-Rbm38 axis might be explored for extending longevity and for tumor suppression.
57 citations
Cites background from "p73 expression is regulated by RNPC..."
...For example, Rbm38 is able to stabilize both p21 and TAp73 transcripts (5, 7), both of which are known to have an impact on aging (40, 41)....
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TL;DR: The novel properties of DNp73 in the invasion metastasis cascade are described and the comprehensive p73 regulatome is outlined with an emphasis on molecular processes putting TAp73 out of action in advanced tumors to provoke a new understanding of the acquisition of aggressive traits by cancer cells.
Abstract: p73 is the older sibling of p53 and mimics most of its tumor-suppressor functions. Through alternative promoter usage and splicing, the TP73 gene generates more than two dozen isoforms of which N-terminal truncated DNp73 variants have a decisive role in cancer pathogenesis as they outweigh the positive effects of full-length TAp73 and p53 in acting as a barrier to tumor development. Beyond the prevailing view that DNp73 predominantly counteract cell cycle arrest and apoptosis, latest progress indicates that these isoforms acquire novel functions in epithelial-to-mesenchymal transition, metastasis and therapy resistance. New insight into the mechanisms underlying this behavior reinforced the expectation that DNp73 variants contribute to aggressive cellular traits through both loss of wild-type tumor-suppressor activity and gain-of-function, suggesting an equally important role in cancer progression as mutant p53. In this review, we describe the novel properties of DNp73 in the invasion metastasis cascade and outline the comprehensive p73 regulatome with an emphasis on molecular processes putting TAp73 out of action in advanced tumors. These intriguing insights provoke a new understanding of the acquisition of aggressive traits by cancer cells and may help to set novel therapies for a broad range of metastatic tumors.
53 citations
TL;DR: The RNA-binding protein (RBP) RNPC1 is a target of the p53 family and forms a feedback regulatory loop with the p 53 family proteins and is able to destabilize the MDM2 transcript via binding to multiple AU-/U-rich elements inMDM2 3′untranslated region (3′UTR).
Abstract: The RNA-binding protein (RBP) RNPC1 is a target of the p53 family and forms a feedback regulatory loop with the p53 family proteins. The murine double minute-2 (MDM2) oncogene, a key negative regulator of p53, has a critical role in a variety of fundamental cellular processes. MDM2 expression is found to be regulated via gene amplification, transcription, protein translation and protein stability. In the current study, we reported a novel regulation of MDM2 by RNPC1 via mRNA stability. Specifically, we found that overexpression of RNPC1 decreases, whereas knockdown or knockout of RNPC1 increases, the level of MDM2 transcript and protein independent of p53. To uncover the underlying mechanism, we found that RNPC1 is able to destabilize the MDM2 transcript via binding to multiple AU-/U-rich elements in MDM2 3′untranslated region (3′UTR). Consistent with this, we showed that RNPC1 inhibits expression of exogenous MDM2 from an expression vector as long as the vector contains an AU-/U-rich element from MDM2 3′UTR. Finally, we showed that the RNA-binding activity of RNPC1 is required for binding to MDM2 transcript and consequently, for inhibiting MDM2 expression. Together, we uncover a novel regulation of MDM2 by the RBP RNPC1 via mRNA stability.
50 citations
References
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TL;DR: The demonstration that p73 is monoallelically expressed supports the notion that it is a candidate gene in neuroblastoma and proposes that the disregulation of p73 contributes to tumorigenesis and that p53-related proteins operate in a network of developmental and cell cycle controls.
1,672 citations
"p73 expression is regulated by RNPC..." refers background in this paper
...TAp73 and possibly p53 since the DNA binding domain shared by TAp73 and Np73 is highly similar to the p53 DNA binding domain (18)....
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TL;DR: It is shown that mice functionally deficient for all p73 isoforms exhibit profound defects, including hippocampal dysgenesis, hydrocephalus, chronic infections and inflammation, as well as abnormalities in pheromone sensory pathways, and there is a marked divergence in the physiological functions of the p53 family members.
Abstract: p73 (ref. 1) has high homology with the tumour suppressor p53 (refs 2,3,4), as well as with p63, a gene implicated in the maintenance of epithelial stem cells5,6,7. Despite the localization of the p73 gene to chromosome 1p36.3, a region of frequent aberration in a wide range of human cancers1, and the ability of p73 to transactivate p53 target genes1, it is unclear whether p73 functions as a tumour suppressor. Here we show that mice functionally deficient for all p73 isoforms exhibit profound defects, including hippocampal dysgenesis, hydrocephalus, chronic infections and inflammation, as well as abnormalities in pheromone sensory pathways. In contrast to p53-deficient mice, however, those lacking p73 show no increased susceptibility to spontaneous tumorigenesis. We report the mechanistic basis of the hippocampal dysgenesis and the loss of pheromone responses, and show that new, potentially dominant-negative, p73 variants are the predominant expression products of this gene in developing and adult tissues. Our data suggest that there is a marked divergence in the physiological functions of the p53 family members, and reveal unique roles for p73 in neurogenesis, sensory pathways and homeostatic control.
1,019 citations
"p73 expression is regulated by RNPC..." refers background in this paper
...In addition, while p53-null mice develop spontaneous tumors, p73-null mice die from developmental defects (40)....
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TL;DR: The results indicate that c-Abl and p73 are components of a mismatch-repair-dependent apoptosis pathway which contributes to cisplatin-induced cytotoxicity.
Abstract: The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage
917 citations
"p73 expression is regulated by RNPC..." refers background in this paper
...p73 is also found to be regulated by acetylation via CBP/p300 (8) and phosphorylation via c-abl (1, 11, 41) and p38 mitogenactivated protein kinase (MAPK) (2)....
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TL;DR: It is concluded that activation of p73 provides a means for E2F-1 to induce death in the absence of p53, and the transcription of the p53 homologue p73 is induced.
Abstract: The transcription factor E2F-1 induces both cell-cycle progression and, in certain settings, apoptosis. E2F-1 uses both p53-dependent and p53-independent pathways to kill cells1,2,3,4,5,6,7,8. The p53-dependent pathway involves the induction by E2F-1 of the human tumour-suppressor protein p14ARF, which neutralizes HDM2 (human homologue of MDM2) and thereby stabilizes the p53 protein9. Here we show that E2F-1 induces the transcription of the p53 homologue p73. Disruption of p73 function inhibited E2F-1-induced apoptosis in p53-defective tumour cells and in p53-/- mouse embryo fibroblasts. We conclude that activation of p73 provides a means for E2F-1 to induce death in the absence of p53.
645 citations
"p73 expression is regulated by RNPC..." refers background or result in this paper
...In addition, p73 can be transcriptionally regulated by DNA damage at least in part via p53, E2F1, and p73 itself (4, 16, 17, 33)....
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...2D to G, compare the control columns with and without camptothecin treatment), consistent with previous reports that p73 transcripts can be upregulated by DNA damage (4, 16)....
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TL;DR: It is concluded that defects in RNA metabolism caused by aberrations in RBPs might underlie a broader spectrum of complex human disorders.
641 citations
"p73 expression is regulated by RNPC..." refers background in this paper
...This family contains one or more canonical RRMs, which are each composed of 80 to 90 amino acids and form a highly conserved modular structure (RNP1 and RNP2) and several conserved aromatic residues (21, 46)....
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