PAK1IP1, a ribosomal stress-induced nucleolar protein, regulates cell proliferation via the p53–MDM2 loop

Yu, Weishi; Qiu, Zhongwei; Gao, Na; Wang, Liren; Cui, Heping; Qian, Yu; Jiang, Li; Luo, Jian; Yi, Zhengfang; Lu, Hua; Li, Dali; Liu, Mingyao

doi:10.1093/nar/gkq1117

Cited by 35 publications

(39 citation statements)

References 54 publications

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“…However, little research has focused on PAK1IP1. In a recent study, Yu et al found that PAK1IP1 was upregulated when cancer cells were suffering from ribosomal stresses and overexpression of PAK1IP1 could inhibit proliferation via p53-MDM2 loop (34). In the present study, PAK1IP1 expression was ~3-fold upregulated in β-elemenetreated gastric cancer cells.…”

Section: Discussionsupporting

confidence: 57%

Anticancer effects of β-elemene in gastric cancer cells and its potential underlying proteins: A proteomic study

Liu

Zhang

et al. 2014

Oncology Reports

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Abstract. Gastric cancer is a common malignancy with a poor prognosis. β-elemene is a broad-spectrum anticancer drug extracted from the traditional Chinese medicinal herb Curcuma wenyujin. In the present study, we investigated the anticancer effects of β-elemene in gastric cancer cells and the potential proteins involved. Human SGC7901 and MKN45 gastric cancer cells were treated with different concentrations of β-elemene. Cell viability, clonogenic survival and apoptotic cell death were assessed. β-elemene inhibited viability and decreased clonogenic survival of gastric cancer cells in a dose-dependent manner. Apoptosis induction contributed to the anticancer effects. We then employed a proteomic method, isobaric tags for relative and absolute quantitation (iTRAQ), to detect the proteins altered by β-elemene. In total, 147 upregulated proteins and 86 downregulated proteins were identified in response to β-elemene treatment in SGC7901 gastric cancer cells. Among them, expression of p21-activated protein kinase-interacting protein 1 (PAK1IP1), Bcl-2-associated transcription factor 1 (BTF) and topoisomerase 2-α (TOPIIα) were validated by western blot analyses and the trends were consistent with iTRAQ results. Top pathways involved in β-elemene treatment in SGC7901 gastric cancer cells included ribosome signaling, peroxisome proliferator-activated receptors (PPARs) signaling pathway, regulation of actin cytoskeleton, phagosome, biosynthesis and metabolism of some amino acids. Collectively, our results suggest a promising therapeutic role of β-elemene in gastric cancer. The differentially expressed proteins provide further insight into the potential mechanisms involved in gastric cancer treatment using β-elemene.

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Section: Discussionsupporting

confidence: 57%

Anticancer effects of β-elemene in gastric cancer cells and its potential underlying proteins: A proteomic study

Liu

Zhang

et al. 2014

Oncology Reports

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“…In previous studies, Pak1ip1 has been shown to localize to the nucleolus and participate in ribosome biogenesis [19], [20]. Indeed, the overall reduction in size of homozygous mray mutants could be well explained by a general deficit in protein biosynthesis resulting in a prolonged cell cycle or even cell cycle arrest and reduced growth.…”

Section: Resultsmentioning

confidence: 94%

“…Pak1ip1 has been implicated in the regulation of both cytoskeletal regulation through the inhibition of the serine/threonine kinase Pak1 [15], [16] and ribosome biogenesis [19], [20]. The multiple and complex cellular functions Pak1ip1 may mediate, presents a challenge in understanding the molecular and cellular mechanisms underlying the median cleft in the mray/mray animals.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, more recent research has shown that Pak1ip1 also localizes to the nucleolus where it is involved in ribosome biogenesis, in light of which its interaction with Pak1 and the cellular events it mediates through this function appear secondary [19]. By facilitating ribosomal RNA processing, Pak1ip1 plays a regulatory role in cell growth and proliferation apparently through direct interaction with the tumor protein 53 (Tp53)-murine double minute 2 (Mdm2) loop upon cellular stress [20]. Furthermore, by causing craniofacial anomalies if mutated, Pak1ip1 joins a group of molecules causative in ribosomopathies associated with craniofacial defects.…”

Section: Introductionmentioning

confidence: 99%

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A Mutation in Mouse Pak1ip1 Causes Orofacial Clefting while Human PAK1IP1 Maps to 6p24 Translocation Breaking Points Associated with Orofacial Clefting

et al. 2013

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Orofacial clefts are among the most common birth defects and result in an improper formation of the mouth or the roof of the mouth. Monosomy of the distal aspect of human chromosome 6p has been recognized as causative in congenital malformations affecting the brain and cranial skeleton including orofacial clefts. Among the genes located in this region is PAK1IP1, which encodes a nucleolar factor involved in ribosomal stress response. Here, we report the identification of a novel mouse line that carries a point mutation in the Pak1ip1 gene. Homozygous mutants show severe developmental defects of the brain and craniofacial skeleton, including a median orofacial cleft. We recovered this line of mice in a forward genetic screen and named the allele manta-ray (mray). Our findings prompted us to examine human cases of orofacial clefting for mutations in the PAK1IP1 gene or association with the locus. No deleterious variants in the PAK1IP1 gene coding region were recognized, however, we identified a borderline association effect for SNP rs494723 suggesting a possible role for the PAK1IP1 gene in human orofacial clefting.

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“…This stress can be caused by any chemical reagents or genetic, molecular and cellular events that disrupt each step of ribosomal biogenesis. These reagents and events include treatment of cells with low dose of actinomycin D (Act D) (15), 5-fluorouracil (16, 17), or mycophenolic acid (MPA) (18), serum starvation or contact inhibition (19), impairment of 40S or 60S ribosomal biogenesis by knockdown of either ribosomal protein (RP) S6 (20) or RPL29 and RPL30 (21), defects in 18S or 28S RNA processing (22), malfunction of nucleolar proteins, such as Bop1 (23), involved in ribosome biogenesis, inhibition of B23 (also known as nucleophosmin) activity by ARF (24), or ablation of nucleostemin by siRNAs (25), and knockdown of PAK1IP1, a nucleolar protein important for rRNA processing (26). Interestingly, it has been recently shown that ribosomal stress can also be induced by genotoxic insults, such as cisplatin or UV irradiation, probably through degradation of RPL37 (27).…”

Section: Introductionmentioning

confidence: 99%

Ribosomal protein S14 unties the MDM2–p53 loop upon ribosomal stress

et al. 2012

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The MDM2-p53 feedback loop is crucially important for restricting p53 level and activity during normal cell growth and proliferation, and is thus subjected to dynamic regulation in order for cells to activate p53 upon various stress signals. Several ribosomal proteins, such as RPL11, RPL5, RPL23, RPL26, or RPS7, have been shown to play a role in regulation of this feedback loop in response to ribosomal stress. Here, we identify another ribosomal protein S14, which is highly associated with 5q-syndrome, as a novel activator of p53 by inhibiting MDM2 activity. We found that RPS14, but not RPS19, binds to the central acidic domain of MDM2, like RPL5 and RPL23, and inhibits its E3 ubiquitin ligase activity toward p53. This RPS14-MDM2 binding was induced upon ribosomal stress caused by actinomycin D or mycophenolic acid. Overexpression of RPS14, but not RPS19, elevated p53 level and activity, leading to G1 or G2 arrest. Conversely, knockdown of RPS14 alleviated p53 induction by these two reagents. Interestingly, knockdown of either RPS14 or RPS19 caused a ribosomal stress that led to p53 activation, which was impaired by further knocking down the level of RPL11 or RPL5. Together, our results demonstrate that RPS14 and RPS19 play distinct roles in regulating the MDM2-p53 feedback loop in response to ribosomal stress.

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PAK1IP1, a ribosomal stress-induced nucleolar protein, regulates cell proliferation via the p53–MDM2 loop

Cited by 35 publications

References 54 publications

Anticancer effects of β-elemene in gastric cancer cells and its potential underlying proteins: A proteomic study

Anticancer effects of β-elemene in gastric cancer cells and its potential underlying proteins: A proteomic study

A Mutation in Mouse Pak1ip1 Causes Orofacial Clefting while Human PAK1IP1 Maps to 6p24 Translocation Breaking Points Associated with Orofacial Clefting

Ribosomal protein S14 unties the MDM2–p53 loop upon ribosomal stress

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