Loss of Peter Pan protein is associated with cell cycle defects and apoptotic events

Keil, Marina; Meyer, M.; Dannheisig, David; Maerz, Lars; Philipp, Melanie; Pfister, Astrid S.

doi:10.1016/j.bbamcr.2019.01.010

Cited by 12 publications

(11 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, severe or continuous stress might drive the cells into apoptosis as a point of no return. In line with this, we have recently shown that pronounced depletion of PPAN increases the pro-apoptotic response in a time-dependent manner [41]. In favor of such a mechanism, a mouse model for nucleolar stress displayed a Huntington’s disease-like phenotype with autophagy induction as initial neuroprotective and life-extending mechanism, preceding apoptosis [8].…”

Section: Discussionmentioning

confidence: 81%

“…Strikingly, these effects were independent of stabilization of the tumor suppressor p53, demonstrating that PPAN orchestrates a novel p53-independent nucleolar stress response [40]. We also found that PPAN knockdown is linked to cell cycle defects and that PPAN depletion induces p53/p21-independent, but caspase-dependent H2A.X phosphorylation [41]. Interestingly, apoptosis induction was prominent in cancer cells, but not detectable in human fibroblasts [41].…”

Section: Introductionmentioning

confidence: 89%

“…We also found that PPAN knockdown is linked to cell cycle defects and that PPAN depletion induces p53/p21-independent, but caspase-dependent H2A.X phosphorylation [41]. Interestingly, apoptosis induction was prominent in cancer cells, but not detectable in human fibroblasts [41].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Loss of Peter Pan (PPAN) Affects Mitochondrial Homeostasis and Autophagic Flux

Dannheisig

Beck

Calzia

et al. 2019

Cells

Self Cite

View full text Add to dashboard Cite

Nucleolar stress is a cellular response to inhibition of ribosome biogenesis or nucleolar disruption leading to cell cycle arrest and/or apoptosis. Emerging evidence points to a tight connection between nucleolar stress and autophagy as a mechanism underlying various diseases such as neurodegeneration and treatment of cancer. Peter Pan (PPAN) functions as a key regulator of ribosome biogenesis. We previously showed that human PPAN localizes to nucleoli and mitochondria and that PPAN knockdown triggers a p53-independent nucleolar stress response culminating in mitochondrial apoptosis. Here, we demonstrate a novel role of PPAN in the regulation of mitochondrial homeostasis and autophagy. Our present study characterizes PPAN as a factor required for maintaining mitochondrial integrity and respiration-coupled ATP production. PPAN interacts with cardiolipin, a lipid of the inner mitochondrial membrane. Down-regulation of PPAN enhances autophagic flux in cancer cells. PPAN knockdown promotes recruitment of the E3-ubiquitin ligase Parkin to damaged mitochondria. Moreover, we provide evidence that PPAN knockdown decreases mitochondrial mass in Parkin-expressing cells. In summary, our study uncovers that PPAN knockdown is linked to mitochondrial damage and stimulates autophagy.

show abstract

Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 89%

See 1 more Smart Citation

Loss of Peter Pan (PPAN) Affects Mitochondrial Homeostasis and Autophagic Flux

Dannheisig

Beck

Calzia

et al. 2019

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

“…H2AX is involved in the recognition of DNA damage and the initiation of a DNA damage response (DDR). Recently, control of genomic stability has been linked to the normal function of the nucleolus, and disruption of the nucleolus is associated to increase in phosphorylation of H2AX (Keil et al, 2019). However, the exact mechanism of POLR3A-mediated P53 and H2AX activation remains to be analyzed in the WRS context.…”

Section: Discussionmentioning

confidence: 99%

Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts

Báez-Becerra

Valencia-Rincón

Velásquez-Méndez

et al. 2020

Mechanisms of Ageing and Development

View full text Add to dashboard Cite

Recently, mutations in the RNA polymerase III subunit 3A (POLR3A) have been described as the cause of the neonatal progeria or Wiedemann-Rautenstrauch syndrome (WRS). POLR3A have important roles in the regulation of transcription of small RNAs, including tRNA, 5S rRNA and U6 snRNA. We aim to describe cellular and molecular features of WRS fibroblasts. Cultures of primary fibroblasts from one WRS patient [monoallelic POLR3A variant c.3772_3773delCT (p.Leu1258Glyfs*12)] and one control were grown. Mutation in POLR3A causes a decreased in the expression of POLR3A mRNA and protein and a sharp increased of mutant protein.In addition, there was an increased in its nuclear localization. These changes were associated to an increase number and area of nucleoli, a significantly larger nuclear area, and a high increased in the expression of pP53 and pH2AX. All these changes were associated to premature senescence. The present observations add to our understanding of the differences between HGPS and WRS, and opens new alternatives to study cell senesce and human aging.

show abstract

“…The following siRNAs were Flexitube siRNAs from Qiagen (Hilden, Germany): si PPAN-A (SI00125545) [ 25 , 34 , 38 , 39 ], si SBDS-C (SI00711144) and si SBDS-D (SI03246390) [ 25 ], si UBF-A (SI00754992) and si UBF-B (SI04290839). Following custom si RNA sequences were previously reported [ 25 , 34 , 38 , 39 ] and were obtained from Horizon Discovery (Lafayette, CO, USA). The respective si RNA sequences are listed below:…”

Section: Methodsmentioning

confidence: 99%

Nucleolar Stress Functions Upstream to Stimulate Expression of Autophagy Regulators

Dannheisig

Schimansky

Donow

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

Ribosome biogenesis is essential for protein synthesis, cell growth and survival. The process takes places in nucleoli and is orchestrated by various proteins, among them RNA polymerases I–III as well as ribosome biogenesis factors. Perturbation of ribosome biogenesis activates the nucleolar stress response, which classically triggers cell cycle arrest and apoptosis. Nucleolar stress is utilized in modern anti-cancer therapies, however, also contributes to the development of various pathologies, including cancer. Growing evidence suggests that nucleolar stress stimulates compensatory cascades, for instance bulk autophagy. However, underlying mechanisms are poorly understood. Here we demonstrate that induction of nucleolar stress activates expression of key autophagic regulators such as ATG7 and ATG16L1, essential for generation of autophagosomes. We show that knockdown of the ribosomopathy factor SBDS, or of key ribosome biogenesis factors (PPAN, NPM, PES1) is associated with enhanced levels of ATG7 in cancer cells. The same holds true when interfering with RNA polymerase I function by either pharmacological inhibition (CX-5461) or depletion of the transcription factor UBF-1. Moreover, we demonstrate that RNA pol I inhibition by CX-5461 stimulates autophagic flux. Together, our data establish that nucleolar stress affects transcriptional regulation of autophagy. Given the contribution of both axes in propagation or cure of cancer, our data uncover a connection that might be targeted in future.

show abstract

Loss of Peter Pan protein is associated with cell cycle defects and apoptotic events

Cited by 12 publications

References 78 publications

Loss of Peter Pan (PPAN) Affects Mitochondrial Homeostasis and Autophagic Flux

Loss of Peter Pan (PPAN) Affects Mitochondrial Homeostasis and Autophagic Flux

Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts

Nucleolar Stress Functions Upstream to Stimulate Expression of Autophagy Regulators

Contact Info

Product

Resources

About