DOR/Tp53inp2 and Tp53inp1 Constitute a Metazoan Gene Family Encoding Dual Regulators of Autophagy and Transcription

Sancho, Ana; Durán, Jordi; Garcı́a-España, Antonio; Mauvezin, Caroline; Alemu, Endalkachew Ashenafi; Lamark, Trond; Macias, María J.; DeSalle, Rob; Royo, Míriam; Sala, David; Chicote, Javier U.; Palacı́n, Manuel; Johansen, Terje; Zorzano, António

doi:10.1371/journal.pone.0034034

Cited by 53 publications

(57 citation statements)

References 37 publications

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“…We and others have characterized the importance of TP53INP1 in macroautophagy. 27,28 We previously showed that TP53INP1 colocalizes with LC3 (microtubuleassociated protein light chain 3) in autophagosomes and also increases the number of autophagosomes in the cytoplasm Where indicated, the WT or K113R mutant TP53INP1a was co-transfected with the previous constructs. Sixteen hours later, cells were exposed to H 2 O 2 1 mM for 1 h, and incubated for an additional 24-h period, luciferase activity was measured in cell lysates.…”

Section: Resultsmentioning

confidence: 99%

Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation

et al. 2014

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Tumor Protein p53-Induced Nuclear Protein 1 (TP53INP1) is a tumor suppressor that modulates the p53 response to stress. TP53INP1 is one of the key mediators of p53 antioxidant function by promoting the p53 transcriptional activity on its target genes. TP53INP1 expression is deregulated in many types of cancers including pancreatic ductal adenocarcinoma in which its decrease occurs early during the preneoplastic development. In this work, we report that redox-dependent induction of p53 transcriptional activity is enhanced by the oxidative stress-induced SUMOylation of TP53INP1 at lysine 113. This SUMOylation is mediated by PIAS3 and CBX4, two SUMO ligases especially related to the p53 activation upon DNA damage. Importantly, this modification is reversed by three SUMO1-specific proteases SENP1, 2 and 6. Moreover, TP53INP1 SUMOylation induces its binding to p53 in the nucleus under oxidative stress conditions. TP53INP1 mutation at lysine 113 prevents the pro-apoptotic, antiproliferative and antioxidant effects of TP53INP1 by impairing the p53 response on its target genes p21, Bax and PUMA. We conclude that TP53INP1 SUMOylation is essential for the regulation of p53 activity induced by oxidative stress. Cell Death and Differentiation (2014) 21, 1107-1118; doi:10.1038/cdd.2014.28; published online 7 March 2014Maintaining homeostasis in response to the broad range of intrinsic and extrinsic aggressions is a challenge for cells. Cellular outcomes are varied and involve cell-cycle arrest, apoptosis, DNA repair, autophagy, senescence, antioxidant activity, cell migration, differentiation, embryo implantation, metabolism and angiogenesis.1-9 An inadequate cell response can lead to cellular transformation and cancer initialization. Tumor Protein p53-Induced Nuclear Protein 1 (TP53INP1) is a p53 cofactor. The gene TP53INP1 encodes for two protein isoforms generated by alternative splicing, named TP53INP1a and TP53INP1b. TP53INP1 is a p53 target gene and its expression is induced in response to several physical and chemical stresses.10-12 TP53INP1 directly interacts with p53 and also binds kinases, such as HIPK2 and PKCd, which modulate p53 transcriptional activity by phosphorylation, thereby creating a positive feedback loop between p53 and TP53INP1.13,14 Our laboratory demonstrated the role of TP53INP1 as a tumor suppressor as TP53INP1-deficient mice present an increased susceptibility to tumor development. Moreover, TP53INP1 expression is lost at very early steps of pancreatic carcinogenesis due to miR155 activity and, when its expression is restored in pancreatic cancer cells, it suppresses growth of xenograft tumors by favoring apoptotic cell death. 15,16 Interestingly, the role of TP53INP1 as a tumor suppressor is associated with its ability to enhance the p53 antioxidant function. 17 In accordance, TP53INP1 transcriptional induction upon oxidative stress is strictly dependent on p53, and TP53INP1-deficient cells accumulate more intracellular reactive oxygen species (ROS) than wild-type cells. This ROS accumulation is...

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Section: Resultsmentioning

confidence: 99%

Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation

et al. 2014

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“…Recently, TP53INP1 is found to be a regulator of autophagy (15). TP53INP1 is reported to interact with ATG8-family proteins and LC3 to induce autophagy-dependent cell death (29).…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we demonstrated that miR-221 inhibited autophagy activity in CRC cells and targeted tumor protein 53-induced nuclear protein 1 (TP53INP1), a regulator of autophagy (15).…”

Section: Mir-221 Inhibits Autophagy and Targets Tp53inp1mentioning

confidence: 91%

“…Among the predicted targets of hsa-miR-221 by the three programs, 446 miRNA-regulated target genes were identified by Targetscan, 5,670 transcripts were identified by miRanda, and 10,184 transcripts by RNA 22. We focused our attention on TP53INP1, which is a regulator of autophagy (15). Western blot analysis showed that the protein expression of TP53INP1 was low in HCT116 cells and high in CACO2 and SW620 cells (Fig.…”

Section: Tp53inp1 Is a Target Of Mir-221mentioning

confidence: 99%

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miR‑221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells

Liao¹,

Li²,

Ye³

et al. 2017

Exp Ther Med

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Abstract. Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-associated mortalities worldwide. MicroRNAs (miRNAs/miRs) serve important roles in tumor development, progression and metastasis. miR-221 has been reported to modulate proliferation, apoptosis, cell cycle distribution and cell migration in a variety of cancers. However, the function of miR-221 in the autophagy of cancer is unclear. In the present study, the role of miR-221 in the autophagy of CRC cells was investigated and its associated target was identified. Survival analysis using The Cancer Genome Atlas data suggested that a higher expression of miR-221 was associated with poor survival in patients with CRC. A Cell Counting kit-8 assay revealed that miR-221 promoted CRC cell proliferation. Autophagy flux analyzed by microtubule-associated protein 1 light chain 3 (LC3) turnover indicated that miR-221 reduced autophagy in CRC cells using different protease inhibitors (E64d and pepstatin A; Bafilomycin A1) in nutrient-rich medium or under starvation conditions. Tumor protein 53-induced nuclear protein 1 (TP53INP1) was identified as a potential novel target of miR-221 by bioinformative prediction. The protein expression of TP53INP1 was inversely regulated by miR-221 in CRC cells. Furthermore, luciferase activity assays were performed and indicated that miR-221 may regulate the luciferase activity of wild-type TP53INP1 without interfering with the activity of mutant TP53INP1. These data suggested that miR-221 may promote the cell proliferation of CRC via the inhibition of autophagy and targeted TP53INP1. IntroductionColorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-associated death worldwide (1). The morbidity rates of CRC are increasing substantially in a number of countries within Eastern Asia and Eastern Europe which were previously at low risk (2). The multifactorial etiology of CRC involves lifestyle and dietary factors, such as smoking, red and processed meat consumption, and excessive alcohol consumption (3). Autophagy is a vital transformational switch among mechanisms that are involved in the pathogenesis of CRC (4). Autophagy may act as a suppressor during early stages and as a promoter during advanced stages of CRC (4,5). It is important to determine the regulative mechanisms of autophagy in CRC.Recent studies suggests that the post-transcription and translation regulation mediated by microRNAs (miRNAs/miRs) contribute significantly to autophagy in cancer (6). It is found that miR-23b-3p inhibits autophagy in gastric cancer cells (7) and miR-26 suppresses autophagy in hepatocellular carcinoma cells (8). Whereas miR-193b is suggested to induce autophagy in oesophageal cancer cells (9). It is interesting that different miRNAs play diverse roles in the regulation of autophagy through various targets.

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“…ASPH is also thought to play an important role in calcium homeostasis [132]. Trp53inp1 encodes an antiproliferative and proapoptotic protein (tumor protein p53-inducible nuclear protein 1) that is involved in cell stress responses by acting as a dual regulator of transcription and autophagy [133][134][135]. TRP53INP1 protein also reduces cell migration by regulating expression of SPARC, a regulator of cell growth through interactions with the extracellular matrix and cytokines.…”

Section: Discussionmentioning

confidence: 99%

Genetic Control of Survival and Weight Loss during Pneumonic Burkholderia pseudomallei (Bp) Infection

Emery¹

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DOR/Tp53inp2 and Tp53inp1 Constitute a Metazoan Gene Family Encoding Dual Regulators of Autophagy and Transcription

Cited by 53 publications

References 37 publications

Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation

Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation

miR‑221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells

Genetic Control of Survival and Weight Loss during Pneumonic Burkholderia pseudomallei (Bp) Infection

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