Angiogenic factor AGGF1 acts as a tumor suppressor by modulating p53 post-transcriptional modifications and stability via MDM2

Si, Wenxia; Zhou, Boru; Xie, Wen; Li, Hui; Li, Ké; Li, Sisi; Deng, Wenbing; Shi, Pengcheng; Yuan, Chao; Ke, Tie; Ren, Xiang; Tu, Xin; Zeng, Xiaomei; Weigelt, Britta; Rubin, Brian P.; Chen, Qiuyun; Xu, Chengqi; Wang, Qing K

doi:10.1016/j.canlet.2020.10.014

Cited by 18 publications

(26 citation statements)

References 38 publications

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“…( 26 ) showed that p53 overexpression transgenic mice under ApoE KO background showed attenuated neointimal formation in mechanically injured femoral arteries. We recently reported that AGGF1 increased p53 stability by interacting with p53, increasing phosphorylation and acetylation of p53, and inhibiting p53 ubiquitination ( 27 ). Therefore, AGGF1 may inhibit neointimal formation after vascular injury through increased p53 expression.…”

Section: Discussionmentioning

confidence: 99%

Angiogenic factor AGGF1 blocks neointimal formation after vascular injury via interaction with integrin α7 on vascular smooth muscle cells

Peng

et al. 2022

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Angiogenic factor AGGF1 blocks neointimal formation after vascular injury via interaction with integrin α7 on vascular smooth muscle cells

Peng

et al. 2022

Journal of Biological Chemistry

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“…19 We recently reported that AGGF1 interacts with p53 through the FHA domain, and modulates p53-mediated transcription activation by stabilizing p53 as a chaperone. 23 It is possible that AGGF1 upregulates NEAT1_2, also through stabilizing p53.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of a special type of subnuclear structure: AGGF1‐coated paraspeckles

et al. 2022

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AGGF1 is an angiogenic factor with G‐Patch and FHA domains 1 described by our group. Gain‐of‐function mutations in AGGF1 cause Klippel–Trenaunay syndrome, whereas somatic loss‐of‐function mutations cause cancer. Paraspeckles are small membraneless subnuclear structures with a diameter of 0.5–1 μm, and composed of lncRNA NEAT1 as the scaffold and three core RNA‐binding proteins NONO, PSPC1, and PSF. Here, we show that AGGF1 is a key regulatory and structural component of paraspeckles that induces paraspeckle formation, forms an outside rim of paraspeckles, wraps around the NONO/PSF/PSPC1/NEAT1 core, and regulates the size and number of paraspeckles. AGGF1‐paraspeckles are larger (>1 μm) than conventional paraspeckles. RNA‐FISH in combination with immunostaining shows that AGGF1, NONO, and NEAT1_2 co‐localize in 20.58% of NEAT1_2‐positive paraspeckles. Mechanistically, AGGF1 interacts with NONO, PSF, and HNRNPK, and upregulates NEAT1_2, a longer, 23 kb NEAT1 transcript with a key role in regulation of paraspeckle size and number. RNA‐immunoprecipitation shows that AGGF1 interacts with NEAT1, which may be another possible mechanism underlying the formation of AGGF1‐paraspeckles. NEAT1_2 knockdown reduces the number and size of AGGF1‐paraspeckles. Functionally, AGGF1 regulates alternative RNA splicing as it decreases the exon skipping/inclusion ratio in a CD44 model. AGGF1 is also localized in some nuclear foci without NEAT1 or NONO, suggesting that AGGF1 is an important liquid–liquid phase separation (LLPS) driver for other types of AGGF1‐positive nuclear condensates (referred to as AGGF1‐bodies). Our results identify a special type of AGGF1‐coated paraspeckles and provide important insights into the formation, structure, and function of paraspeckles.

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“…The stability of p53 is carefully regulated by the ubiquitin-proteasome system and p53 levels are finely tuned to respond to stressful conditions ( Leu et al, 2020 ). Ubiquitination plays a role in the regulation of p53 expression for the regulation of cell cycle progression ( Si et al, 2021 ). We examined the mechanism by which ZWINT regulated p53 expression and found that ZWINT inhibited p53 only at the protein level.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced ZWINT Mediates Pancreatic Cancer Proliferation by Interacting With p53/p21

Chen

Wang

et al. 2021

Front. Cell Dev. Biol.

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p53/p21 signaling plays a vital role in pancreatic cancer (PC) progression. ZWINT was shown to function as an oncoprotein in the progression of multiple cancers. However, the involvement of ZWINT and p53 activation in the progression of PC remains poorly understood. Bioinformatics and tissue array chip analyses were performed to evaluate ZWINT expression in pancreatic cancer. ZWINT mRNA and protein expression were evaluated in normoxia and hypoxia. CHIP was used to evaluate HIF1α interaction with the ZWINT promoter. CCK8, colony formation, EDU, and cell cycle analysis were used to examine PC cell proliferation. Immunoprecipitation and immunofluorescence were used to examine the interaction of ZWINT, MDM2, and p53. p53 activity was evaluated by q-PCR and luciferase assay. Protein degradation and ubiquitination assays were used to analyze the role of ZWINT in p53 ubiquitination. ZWINT was overexpressed in pancreatic cancer and induced in hypoxia. ZWINT promoted pancreatic cancer growth and cell cycle progression. Bioinformatic analysis revealed that ZWINT may regulate the p53 signal pathway. ZWINT interacts with p53 and promotes its ubiquitination and degradation. ZWINT promoted proliferation via p53/p21. Immunohistochemistry of clinical specimens revealed that that ZWINT expression was significantly negatively correlated with p53/p21. Our data showed that hypoxia regulates the expression of ZWINT, which activated p53/p21 signaling pathway to promote PC growth.

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Angiogenic factor AGGF1 acts as a tumor suppressor by modulating p53 post-transcriptional modifications and stability via MDM2

Cited by 18 publications

References 38 publications

Angiogenic factor AGGF1 blocks neointimal formation after vascular injury via interaction with integrin α7 on vascular smooth muscle cells

Angiogenic factor AGGF1 blocks neointimal formation after vascular injury via interaction with integrin α7 on vascular smooth muscle cells

Identification and characterization of a special type of subnuclear structure: AGGF1‐coated paraspeckles

Hypoxia-Induced ZWINT Mediates Pancreatic Cancer Proliferation by Interacting With p53/p21

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