Endogenous p53 expression in human and mouse is not regulated by its 3′UTR

Mitschka, Sibylle; Mayr, Christine

doi:10.1101/2020.11.23.394197

Cited by 3 publications

(4 citation statements)

References 44 publications

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“…The two TP53 constructs produced similar induced levels of p53 protein (Fig. 1a), indicating that the 3’UTR does not appreciably affect p53 expression, consistent with a recent report 21 . As expected, TP53 CR induction substantially reduced cell proliferation.…”

Section: Resultssupporting

confidence: 91%

3’UTR-dependent dynamic changes in TP53 mRNA localization regulate p53 tumor suppressor activity

Misra

Karim

et al. 2022

Preprint

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The tumor suppressor p53 triggers senescence in response to oncogenic stress in primary cells. However, the mechanisms by which tumor cells retaining p53 bypass senescence are not fully understood. Here we report that p53 cytostatic activity is inhibited in tumor cells by the 3' untranslated region (3'UTR) of its mRNA, without altering p53 levels. 3'UTR inhibition requires a long U-rich element (URE) and its binding protein, HuR. The 3'UTR excluded TP53 mRNAs from a perinuclear compartment containing the CK2 kinase, suppressing p53 phosphorylation on an activating CK2 site, Ser392. In primary cells undergoing oncogene-induced senescence and tumor cells treated with genotoxic agents, TP53 mRNAs became concentrated in the perinuclear cytoplasm, coinciding with p53 phosphorylation and activation by CK2. In both cases, perinuclear re-localization of TP53 transcripts required AMPKα2-dependent HuR nuclear translocation. ATM kinase activity was essential for DNA damage-induced spatial reprogramming of TP53 mRNAs, likely through phosphorylation and inactivation of MDM2. MDM2 was required for peripheral localization of TP53 transcripts and negatively regulated levels of the AMPKα2 activating kinase, CaMKKβ. Our findings reveal a critical role for 3'UTR sequences in suppressing p53 protein activity and provide a new mechanistic framework for p53 activation by DNA damaging agents.

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Section: Resultssupporting

confidence: 91%

3’UTR-dependent dynamic changes in TP53 mRNA localization regulate p53 tumor suppressor activity

Misra

Karim

et al. 2022

Preprint

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“…Similarly, p53 contains a natural antisense transcript, designated Wrap53, that regulates endogenous p53 mRNA levels and further induction of p53 protein by targeting the 5′ untranslated region of p53 mRNA (64). Finally, the 3’ UTR of p53 is the target of many different microRNAs, lncRNAs and RNA-binding proteins that could influence mRNA stability (61,65); however the extent to which the 3’ UTR influences Trp53 mRNA half-life has recently been brought into question (66). Nevertheless, differential expression of factors that post-transcriptionally influence p53 mRNA levels in Lmna KO skeletal muscle could be contributing to the increased p53 mRNA levels observed in vivo .…”

Section: Discussionmentioning

confidence: 99%

Eliminating elevated p53 signaling fails to rescue skeletal muscle defects or extend survival in Lamin A/C-deficient mice

Kirby

Zahr

Fong

et al. 2022

Preprint

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Lamins A and C, encoded by the LMNA gene, are nuclear intermediate filaments that provide structural support to the nucleus and contribute to chromatin organization and transcriptional regulation. LMNA mutations cause muscular dystrophies, dilated cardiomyopathy, and other diseases. The mechanisms by which many LMNA mutations result in muscle-specific diseases have remained elusive, presenting a major hurdle in the development of effective treatments. Previous studies using striated muscle laminopathy mouse models found that cytoskeletal forces acting on mechanically fragile Lmna-mutant nuclei led to transient nuclear envelope rupture, extensive DNA damage, and activation of DNA damage response (DDR) pathways in skeletal muscle cells in vitro and in vivo. Furthermore, hearts of Lmna mutant mice have elevated activation of the tumor suppressor protein p53, a central regulator of DDR signaling. We hypothesized that elevated p53 activation could present a pathogenic mechanism in striated muscle laminopathies, and that eliminating p53 activation could improve muscle function and survival in laminopathy mouse models. Supporting a pathogenic function of p53 activation in muscle, stabilization of p53 was sufficient to reduce contractility and viability in wild-type muscle cells in vitro. Using three laminopathy models, we found that increased p53 activity in Lmna-mutant muscle cells primarily resulted from mechanically induced damage to the myonuclei, and not from altered transcriptional regulation due to loss of lamin A/C expression. However, global deletion of p53 in a severe muscle laminopathy model did not reduce the disease phenotype or increase survival, indicating that additional drivers of disease must contribute to the disease pathogenesis.

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“…However, alterations in alternative 3′UTR isoform expression often do not change overall protein levels (Fig. 1) 12,14,20,84,85 . For those cases, it has been demonstrated that isoform-specific differences in protein localization or function occur through 3′UTR-mediated formation of alternative protein complexes [11][12][13][14][15] .…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, malignant B cells preferentially form long 3′UTRdependent protein complexes that have tumor-promoting roles 12 . So far, most studies that investigated the functional consequences of alternative 3′UTR isoform expression have relied on using expression constructs, but more recently CRISPR-mediated deletions of 3′UTRs were added to the tool kit [11][12][13][14][15]25,[84][85][86] . Alternatively, as we showed here, 3′UTR isoform expression can be altered through enhancer deletion (Fig.…”

Section: Discussionmentioning

confidence: 99%

Enhancers regulate 3′ end processing activity to control expression of alternative 3′UTR isoforms

Kwon

Fansler

Patel

et al. 2020

Preprint

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Enhancers are DNA elements that increase gene expression. mRNA production is determined by transcript production and polyadenylation site (PAS) cleavage activity. We established an assay to measure enhancer-dependent PAS cleavage activity in human cells because PAS cleavage may control alternative 3′UTR isoform expression. We found that enhancers are widespread regulators of PAS cleavage and consistently increase cleavage of proximal and weak PAS. Half of tested transcription factors exclusively regulated PAS cleavage without affecting transcript production, whereas co-activators changed both parameters. Deletion of an endogenous enhancer of PTEN did not change gene-level mRNA or protein abundance but affected expression of alternative mRNA transcripts, thus preventing 3′UTR shortening. Our data reveal that in addition to controlling transcript production, enhancers also regulate PAS cleavage, thus changing 3′UTR isoform usage and protein activity, as PTEN proteins translated from the alternative 3′UTR isoforms differ in intrinsic lipid phosphatase activity despite having identical amino acid sequences.

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Endogenous p53 expression in human and mouse is not regulated by its 3′UTR

Cited by 3 publications

References 44 publications

3’UTR-dependent dynamic changes in TP53 mRNA localization regulate p53 tumor suppressor activity

3’UTR-dependent dynamic changes in TP53 mRNA localization regulate p53 tumor suppressor activity

Eliminating elevated p53 signaling fails to rescue skeletal muscle defects or extend survival in Lamin A/C-deficient mice

Enhancers regulate 3′ end processing activity to control expression of alternative 3′UTR isoforms

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