Browse
Submit Data
Databases
API
Help

Dataset Information

37 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

P53 upregulates PLC?-IP3-Ca2+ pathway and inhibits autophagy through its target gene Rap2B.

ABSTRACT: The tumor suppressor p53 plays a pivotal role in numerous cellular responses as it regulates cell proliferation, metabolism, cellular growth, and autophagy. In order to identify novel p53 target genes, we utilized an unbiased microarray approach and identified Rap2B as a robust candidate, which belongs to the Ras-related GTP-binding protein superfamily and exhibits increased expression in various human cancers. We demonstrated that p53 increases the intracellular IP3 and Ca2+ levels and decreases the LC3 protein levels through its target gene Rap2B, suggesting that p53 can inhibit the autophagic response triggered by starvation via upregulation of the Rap2B-PLC?-IP3-Ca2+ pathway. As a confirmed target gene of p53, we believe that further investigating potential functions of Rap2B in autophagy and tumorigenesis will provide a novel strategy for cancer therapy.

SUBMITTER: Di J

PROVIDER: S-EPMC5630284 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

p53 upregulates PLCε-IP3-Ca2+ pathway and inhibits autophagy through its target gene Rap2B.

Di Jiehui J Tang Juanjuan J Qian Heya H Franklin Derek A DA Deisenroth Chad C Itahana Yoko Y Zheng Junnian J Zhang Yanping Y

Oncotarget 20170523 39

The tumor suppressor p53 plays a pivotal role in numerous cellular responses as it regulates cell proliferation, metabolism, cellular growth, and autophagy. In order to identify novel p53 target genes, we utilized an unbiased microarray approach and identified Rap2B as a robust candidate, which belongs to the Ras-related GTP-binding protein superfamily and exhibits increased expression in various human cancers. We demonstrated that p53 increases the intracellular IP3 and Ca2+ l ...[more]

PMID: 29029384

Similar Datasets

Rap2b, a novel p53 target, regulates p53-mediated pro-survival function.

Project description:The tumor suppressor p53 is a critical regulator of apoptosis and cell cycle arrest/pro-survival. Upon DNA damage, p53 evokes both cell cycle arrest/pro-survival and apoptosis transcriptional programs. The ultimate cellular outcome depends on the balance of these two programs. However, the p53 downstream targets that mediate this cell fate decision remain to be identified. Using an integrative genomic approach, we identify Rap2b as a conserved p53-activated gene that counters p53-mediated apoptosis after DNA damage. Upon DNA damage, p53 directly binds to the promoter of Rap2b and activates its transcription. The reduction of Rap2b levels by small interference RNA sensitizes cells to DNA damage-induced apoptosis in a p53-dependent manner. Consistent with its pro-survival function, analysis of cancer genomic data reveals that Rap2b is overexpressed in many types of tumors. Anchorage-independent growth assays show that Rap2b has only weak transformation activity, suggesting that it is not an oncogene by itself. Together, our results identify Rap2b as a new player in the pro-survival program conducted by p53 and raise the possibility that targeting Rap2b could sensitize tumor cells to apoptosis in response to DNA damage.

| S-EPMC3674092 | biostudies-literature

Ca2+-binding protein 2 inhibits Ca2+-channel inactivation in mouse inner hair cells.

Project description:Ca2+-binding protein 2 (CaBP2) inhibits the inactivation of heterologously expressed voltage-gated Ca2+ channels of type 1.3 (CaV1.3) and is defective in human autosomal-recessive deafness 93 (DFNB93). Here, we report a newly identified mutation in CABP2 that causes a moderate hearing impairment likely via nonsense-mediated decay of CABP2-mRNA. To study the mechanism of hearing impairment resulting from CABP2 loss of function, we disrupted Cabp2 in mice (Cabp2LacZ/LacZ ). CaBP2 was expressed by cochlear hair cells, preferentially in inner hair cells (IHCs), and was lacking from the postsynaptic spiral ganglion neurons (SGNs). Cabp2LacZ/LacZ mice displayed intact cochlear amplification but impaired auditory brainstem responses. Patch-clamp recordings from Cabp2LacZ/LacZ IHCs revealed enhanced Ca2+-channel inactivation. The voltage dependence of activation and the number of Ca2+ channels appeared normal in Cabp2LacZ/LacZ mice, as were ribbon synapse counts. Recordings from single SGNs showed reduced spontaneous and sound-evoked firing rates. We propose that CaBP2 inhibits CaV1.3 Ca2+-channel inactivation, and thus sustains the availability of CaV1.3 Ca2+ channels for synaptic sound encoding. Therefore, we conclude that human deafness DFNB93 is an auditory synaptopathy.

| S-EPMC5338518 | biostudies-literature

XIAP inhibits autophagy via XIAP-Mdm2-p53 signalling.

Project description:The primary role of autophagy is adaption to starvation. However, increasing evidence suggests that autophagy inhibition also plays an important role in tumorigenesis. Upregulation of X-linked inhibitor of apoptosis (XIAP) has been associated to a variety of human cancers, yet the underlying mechanisms remain obscure. Here, we report that XIAP suppresses autophagy by exerting a previously unidentified ubiquitin E3 ligase activity towards Mdm2, which is a negative regulator of p53. XIAP controls serum starvation-induced autophagy downstream of the PI3K/Akt pathway. In mouse models, inhibition of autophagy by XIAP promotes tumorigenecity of HCT116 cells. XIAP-mediated autophagy inhibition is also largely validated in clinical tumour samples. These findings reveal a novel XIAP-Mdm2-p53 pathway that mediates the inhibition of autophagy, by which XIAP may contribute to tumorigenesis.

| S-EPMC3746193 | biostudies-literature

Sustained IP3-linked Ca2+ signaling promotes progression of triple negative breast cancer cells by regulating fatty acid metabolism.

Project description:Rewiring of mitochondrial metabolism has been described in different cancers as a key step for their progression. Calcium (Ca2+) signaling regulates mitochondrial function and is known to be altered in several malignancies, including triple negative breast cancer (TNBC). However, whether and how the alterations in Ca2+ signaling contribute to metabolic changes in TNBC has not been elucidated. Here, we found that TNBC cells display frequent, spontaneous inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ oscillations, which are sensed by mitochondria. By combining genetic, pharmacologic and metabolomics approaches, we associated this pathway with the regulation of fatty acid (FA) metabolism. Moreover, we demonstrated that these signaling routes promote TNBC cell migration in vitro, suggesting they might be explored to identify potential therapeutic targets.

| S-EPMC10040683 | biostudies-literature

Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca2+ oscillations in asthma.

Project description:BackgroundAirway hyperresponsiveness is a major feature of asthma attributed predominantly to an extrinsic immune/inflammatory response increasing airway smooth muscle (ASM) contractility.ObjectiveWe investigated whether increased ASM expression of orosomucoid-like 3 (ORMDL3), a gene on chromosome 17q21 highly linked to asthma, induced increased ASM proliferation and contractility in vitro and influenced airway contractility and calcium flux in ASM in precision-cut lung slices (PCLSs) from wild-type and hORMDL3Zp3-Cre mice (which express increased levels of human ORMDL3 [hORMDL3]).MethodsLevels of ASM proliferation and contraction were assessed in ASM cells transfected with ORMDL3 in vitro. In addition, airway contractility and calcium oscillations were quantitated in ASM cells in PCLSs derived from naive wild-type and naive hORMDL3Zp3-Cre mice, which do not have a blood supply.ResultsIncreased ASM expression of ORMDL3 in vitro resulted in increased ASM proliferation and contractility. PCLSs derived from naive hORMDL3Zp3-Cre mice, which do not have airway inflammation, exhibit increased airway contractility with increased calcium oscillations in ASM cells. Increased ASM ORMDL3 expression increases levels of ASM sarcoplasmic reticulum Ca2+ ATPase 2b (SERCA2b), which increases ASM proliferation and contractility.ConclusionOverall, these studies provide evidence that an intrinsic increase in ORMDL3 expression in ASM can induce increased ASM proliferation and contractility, which might contribute to increased airway hyperresponsiveness in the absence of airway inflammation in asthmatic patients.

| S-EPMC5842097 | biostudies-literature

Gastrodin Inhibits Store-Operated Ca2+ Entry and Alleviates Cardiac Hypertrophy.

Project description:Cardiac hypertrophy is a major risk factor for heart failure, which are among the leading causes of human death. Gastrodin is a small molecule that has been used clinically to treat neurological and vascular diseases for many years without safety issues. In the present study, we examined protective effect of gastrodin against cardiac hypertrophy and explored the underlying mechanism. Phenylephrine and angiotensin II were used to induce cardiac hypertrophy in a mouse model and a cultured cardiomyocyte model. Gastrodin was found to alleviate the cardiac hypertrophy in both models. Mechanistically, gastrodin attenuated the store-operated Ca2+ entry (SOCE) by reducing the expression of STIM1 and Orai1, two key proteins in SOCE, in animal models as well as in cultured cardiomyocyte model. Furthermore, suppressing SOCE by RO2959, Orai1-siRNAs or STIM1-siRNAs markedly attenuated the phenylephrine-induced hypertrophy in cultured cardiomyocyte model. Together, these results showed that gastrodin inhibited cardiac hypertrophy and it also reduced the SOCE via its action on the expression of STIM1 and Orai1. Furthermore, suppression of SOCE could reduce the phenylephrine-induced cardiomyocyte hypertrophy, suggesting that SOCE-STIM1-Orai1 is located upstream of hypertrophy.

| S-EPMC5404510 | biostudies-literature

Co-targeting Mitochondrial Ca2+ Homeostasis and Autophagy Enhances Cancer Cells' Chemosensitivity.

Project description:Mitochondria are important cell death checkpoints, and mitochondrial Ca2+ overload is considered as a potent apoptotic intrinsic pathway inducer. Here, we report that this Ca2+ apoptosis link is largely ineffective in inducing cell-death just by itself and required a concomitant inhibition of autophagy to counteract its pro-survival action. In such condition, an acute mitochondrial stress revealed by a DRP1-mediated mitochondrial dynamic remodeling is observed concomitantly with mitochondrial depolarization, release of cytochrome c, and efficient apoptosis induction. We also uncover that mitochondrial Ca2+ status modulates the function of autophagy as a sensitizer for chemotherapies. This priming mediated by mitochondrial Ca2+ overload and inhibition of autophagy sensitizes many cancer cells types to different chemotherapies with independent mechanisms of action. Collectively, our results redefine an important cell signaling pathway, uncovering new combined therapies for the treatment of diseases associated with mitochondrial Ca2+ homeostasis disorders such as cancer.

| S-EPMC7322071 | biostudies-literature

Autophagy inhibition upregulates CD4+ tumor infiltrating lymphocyte expression via miR-155 regulation and TRAIL activation.

Project description:Chemoresistance is a major challenge in lung cancer treatment. Recent findings have revealed that autophagic mechanism contributes significantly to immunosuppressive related chemoresistance. For that reason, targeting autophagy-related immunosuppression is an important approach to reverse tumor drug resistance. In this study, we report for the first time that autophagy inhibition triggers upregulation of CD4+, Foxp3+ tumor infiltrating lymphocytes in late metastatic lung cancer tissues. Furthermore, autophagy blockage induces chemosensitization to carboplatin, immune activation and cell cycle arrest. This induction correlated with reduction in expression of drug resistance genes MDR1, MRP1, ABCG2 and ABCC2 along with decreased expression of PD-L1 which is associated with severe dysfunction of tumor specific CD8+ T cells. Furthermore, experiments revealed that co-treatment of carboplatin and autophagy inhibitor chloroquine increased lung tissue infiltration by CD4+, FoxP3+ lymphocytes and antigen-specific immune activation. Subsequent ex vivo experiments showed the activation of carboplatin related TRAIL-dependent apoptosis through caspase 8 and a synergistic role of miR-155 in lung tissue infiltration by CD4+, and FoxP3+ lymphocytes. Overall, our results indicate that autophagy blockage increases lung cancer chemosensitivity to carboplatin, but also reveal that miR-155 functions as a novel immune system activator by promoting TILs infiltration. These results indicate that targeting of autophagy can prevent cancer related immunosuppression and elucidate immune cell infiltration in tumor microenvironment thus representing a potential therapeutic strategy to inhibit lung cancer progression and metastasis.

| S-EPMC5423126 | biostudies-literature

Pifithrin-? alters p53 post-translational modifications pattern and differentially inhibits p53 target genes.

Project description:Pifithrin-? (PFT-?) is a small molecule which has been widely used as a specific inhibitor of p53 transcription activity. However, its molecular mechanism of action remains unclear. PFT-? has also been described to display potent p53-independent activity in cells. In this study, we addressed the mechanism of action of PFT-?. We found that PFT-? failed to prevent the effects of Mdm2 inhibitor Nutlin-3 on cell cycle and apoptosis in several cancer cell lines. However, PFT-? rescued normal primary fibroblasts from growth inhibition by Nutlin-3. PFT-? displayed a very limited effect on p53-dependent transcription upon its activation by Nutlin-3. Moreover, PFT-? inhibitory effect on transcription was highly dependent on the nature of the p53 target gene. PFT-? attenuated post-translational modifications of p53 without affecting total p53 protein level. Finally, we found that PFT-? can decrease the level of intracellular reactive oxygen species through activation of an aryl hydrocarbon receptor (AHR)-Nrf2 axis in a p53-independent manner. In conclusion, PFT-? inhibits only some aspects of p53 function, therefore it should be used with extreme caution to study p53-dependent processes.

| S-EPMC6978515 | biostudies-literature

Carvedilol inhibits cADPR- and IP3-induced Ca2+ release.

Project description:Spontaneous Ca2+ waves, also termed store-overload-induced Ca2+ release (SOICR), in cardiac cells can trigger ventricular arrhythmias especially in failing hearts. SOICR occurs when RyRs are activated by an increase in sarcoplasmic reticulum (SR) luminal Ca2+. Carvedilol is one of the most effective drugs for preventing arrhythmias in patients with heart failure. Furthermore, carvedilol analogues with minimal β-blocking activity also block SOICR showing that SOICR-inhibiting activity is distinct from that for β-block. We show here that carvedilol is a potent inhibitor of cADPR-induced Ca2+ release in sea urchin egg homogenate. In addition, the carvedilol analog VK-II-86 with minimal β-blocking activity also suppresses cADPR-induced Ca2+ release. Carvedilol appeared to be a non-competitive antagonist of cADPR and could also suppress Ca2+ release by caffeine. These results are consistent with cADPR releasing Ca2+ in sea urchin eggs by sensitizing RyRs to Ca2+ involving a luminal Ca2+ activation mechanism. In addition to action on the RyR, we also observed inhibition of inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release by carvedilol suggesting a common mechanism between these evolutionarily related and conserved Ca2+ release channels.

| S-EPMC5531262 | biostudies-literature