Polyamine Depletion Increases Cytoplasmic Levels of RNA-binding Protein HuR Leading to Stabilization of Nucleophosmin and p53 mRNAs

Zou, Tongtong; Mazan-Mamczarz, Krystyna; Rao, Jaladanki N.; Liu, Lan; Marasa, Bernard S.; Zhang, Aihong; Xiao, Lan; Pullmann, R; Gorospe, Myriam; Wang, Jianying

doi:10.1074/jbc.m602344200

Cited by 114 publications

(185 citation statements)

References 52 publications

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“…One such IRES segment in the 5Ј-UTR of p53 mRNA has been shown to increase translation of p53 mRNA in response to the DNA-damaging agent etoposide (Yang et al, 2006). In addition, the RNA-binding protein HuR was found to stabilize p53 mRNA by binding the 3Ј-UTR in response to polyamine depletion (Zou et al, 2006). Thus, it is clear that mRNA-binding proteins play an important role in p53 expression during cellular stress by both modifying translation and mRNA stability.…”

Section: Discussionmentioning

confidence: 94%

Interaction of Heterogeneous Nuclear Ribonucleoprotein C1/C2 with a Novelcis-Regulatory Element within p53 mRNA as a Response to Cytostatic Drug Treatment

2008

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We describe a novel cis-element in the 5Ј coding region of p53 mRNA and its interaction with heterogeneous nuclear ribonucleoprotein (hnRNP)C1/C2. This element is located in a putative hairpin loop structure, within the first 101 nucleotides downstream of the start codon. The binding of hnRNPC1/C2 is strongly enhanced in response to the DNA-damaging drug cisplatin [cis-diamminedichloroplatinum(II)] and the cytostatic transcriptional inhibitor actinomycin D (dactinomycin), both known inducers of apoptosis and p53. Strongly stimulated binding is observed in both nuclear and cytoplasmic compartments, and it is accompanied by a cytoplasmic increase of hnRNPC1/C2. Changes in hnRNPC1/C2 protein levels are not proportional to binding activity, suggesting qualitative changes in hnRNPC1/C2 upon activation. Phosphorylation studies reveal contrasting characteristics of the cytoplasmic and nuclear hnRNPC1/C2 interaction with p53 mRNA. Results from chimeric p53-luciferase reporter constructs suggest that hnRNPC1/C2 regulates p53 expression via this binding site. Our results are consistent with a mechanism in which the interaction of hnRNPC1/C2 with a cis-element within the coding region of the p53 transcript regulates the expression of p53 mRNA before and during apoptosis. In addition, we report that preapoptotic signals induced by transcriptional inhibition trigger the appearance of a truncated, exclusively cytoplasmic 43-kDa variant of p53 before apoptosis.

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Section: Discussionmentioning

confidence: 94%

Interaction of Heterogeneous Nuclear Ribonucleoprotein C1/C2 with a Novelcis-Regulatory Element within p53 mRNA as a Response to Cytostatic Drug Treatment

2008

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“…The RRM family of RNA-binding proteins is known to recognize a transcript with AU-rich elements (AREs) (22,47). These elements are composed of various copies of the AUUUA pentamer or UUAUUUAUU nonamer (46).…”

Section: Discussionmentioning

confidence: 99%

p73 Expression Is Regulated by RNPC1, a Target of the p53 Family, via mRNA Stability

Yan

Zhang

et al. 2012

Molecular and Cellular Biology

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p73, a p53 family tumor suppressor, is expressed as TA and ⌬N 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 ␥-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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“…Chromatin organization have been shown to regulate translation of specific mRNAs, 24,25 and in intestinal epithelial cells polyamines regulate the RNA binding protein HuR to control target mRNA stability. 26,27 Polyamines have also been shown to regulate gene-specific transcription 28 and kinase activity. 23 The levels of the polyamines are tightly regulated at the level of synthesis, uptake, degradation and secretion.…”

Section: A Role For Polyamine Regulators In Esc Self-renewalmentioning

confidence: 99%

A role for polyamine regulators in ESC self-renewal

Zhao

Goh

et al. 2012

Cell Cycle

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E mbryonic stem cells (ESCs) dependon extensive regulatory networks to coordinate their self-renewal and differentiation. The polyamine pathway regulator AMD1 was recently implicated in ESC self-renewal and directed differentiation of ESCs to neural precursor cells (NPCs). The polyamines spermine and spermidine are essential for a wide range of biological processes, and their levels are tightly regulated. Here, we review the polyamine pathway and discuss how it can impact polyamine levels, cellular methylation and hypusinated EIF5A levels. We discuss how it could feed into regulation of ESC self-renewal and directed differentiation. We show that in addition to AMD1, a second rate-limiting enzyme in the polyamine pathway, ODC1, can also promote ESC self-renewal, and that both Amd1 and Odc1 can partially substitute for Myc during cellular reprogramming. We propose that both Amd1 and Odc1 are essential regulators of ESCs and function to ensure high polyamine levels to promote ESC self-renewal.

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Polyamine Depletion Increases Cytoplasmic Levels of RNA-binding Protein HuR Leading to Stabilization of Nucleophosmin and p53 mRNAs

Cited by 114 publications

References 52 publications

Interaction of Heterogeneous Nuclear Ribonucleoprotein C1/C2 with a Novelcis-Regulatory Element within p53 mRNA as a Response to Cytostatic Drug Treatment

Interaction of Heterogeneous Nuclear Ribonucleoprotein C1/C2 with a Novelcis-Regulatory Element within p53 mRNA as a Response to Cytostatic Drug Treatment

p73 Expression Is Regulated by RNPC1, a Target of the p53 Family, via mRNA Stability

A role for polyamine regulators in ESC self-renewal

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