GD3 Synthase Is a Master Regulator of Wild-Type p53–Mediated Apoptosis and Mutant p53–Mediated Tumorigenesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE248670 | GEO | 2023/12/02
REPOSITORIES: GEO
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Project description:GD3 Synthase Is a Master Regulator of Wild-Type p53–Mediated Apoptosis and Mutant p53–Mediated Tumorigenesis
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Project description:Tumor suppressor p53 plays an essential role in protecting cells from malignant transformation by inducing cell-cycle arrest and apoptosis. Mutant p53 that is detected in more than 50% of cases of cancers loses its role in suppression of tumors but gains in oncogenic function. Strategies to convert mutant p53 into wild-type p53 have been suggested for cancer prevention and treatment, but they face a variety of challenges. Here, we report an alternative approach that involves suppression of glucosylceramide synthase (GCS), an enzyme that glycosylates ceramide and blunts its proapoptotic activity in cancer cells. Human ovarian cancer cells expressing mutant p53 displayed resistance to apoptosis induced by DNA damage. We found that GCS silencing sensitized these mutant p53 cells to doxorubicin but did not affect the sensitivity of cells with wild-type p53. GCS silencing increased the levels of phosphorylated p53 and p53-responsive genes, including p21(Waf1/Cip1), Bax, and Puma, consistent with a redirection of the mutant p53 cells to apoptosis. Reactivated p53-dependent apoptosis was similarly verified in p53-mutant tumors where GCS was silenced. Inhibition of ceramide synthase with fumonisin B1 prevented p53 reactivation induced by GCS silencing, whereas addition of exogenous C6-ceramide reactivated p53 function in p53-mutant cells. Our findings indicate that restoring active ceramide to cells can resuscitate wild-type p53 function in p53-mutant cells, offering preclinical support for a novel type of mechanism-based therapy in the many human cancers harboring p53 mutations.
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Project description:TRAF6 -/- thymi display defects in IR-induced p53 target gene expression and attenuate further enhancement of apoptosis upon IR treatment. TRAF6-mediated K63-linked ubiquitination of p53 at K24
2016-11-04 | GSE69730 | GEO
Project description:Mice engineered with a G12D versus Q61R mutation in Kras exhibited differences in tumorigenesis. Namely, the incidence or grade of oral or forestomach squamous epithelial lesions was more prevalent in the KrasG12D background while hematolymphopoietic disease was more prevalent in the KrasQ61R background. Loss of the Trp53 gene encoding the tumor suppressor p53 enhances the ability of oncogenic Kras to initiate tumorigenesis in carcinogen and genetic models of lung cancer. Conversley, an extra copy of Trp53 (Super p53) was recently shown to suppress Kras-induced tumorigenesis in a genetic model of this disease. Given this, we evaluated whether an extra copy of Trp53 would alter tumorigenesis upon global activation of a modified Kras allele engineered with either a G12D or Q61R mutation. We report that an increase in p53 dosage significantly reduced the incidence or grade of oral and forestomach squamous tumors induced by either G12D and Q61R-mutant Kras. The incidence of myeloproliferative disease was also significantly reduced with increased p53 dosage in the KrasQ61R background. Both the percentage of mice with lung tumors and total number of adenomas per animal were unchanged. However, the incidence and grade of peripheral atypical alveolar hyperplasia was significantly decreased in both backgrounds with increased p53 dosage. Finally, the number of foci of bronchioloalveolar hyperplasia per animal significantly increased with increased p53 dosage in the KrasG12D background. These results suggest that an extra copy of p53 can impede oncogenic Kras driven tumorigenesis in some tissues.
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Project description:A subset of DNA helicases, the RecQ family, has been found to be associated with the p53-mediated apoptotic pathway and is involved in maintaining genomic integrity. This family contains the BLM and WRN helicases, in which germline mutations are responsible for Bloom and Werner syndromes, respectively. TFIIH DNA helicases, XPB and XPD, are also components in this apoptotic pathway. We hypothesized that there may be some redundancy between helicases in their ability to complement the attenuated p53-mediated apoptotic levels seen in cells from individuals with diseases associated with these defective helicase genes. The attenuated apoptotic phenotype in Bloom syndrome cells was rescued not only by ectopic expression of BLM, but also by WRN or XPB, both 3' --> 5' helicases, but not expression of the 5' --> 3' helicase XPD. Overexpression of Sgs1, a WRN/BLM yeast homolog, corrected the reduction in BS cells only, which is consistent with Sgs1 being evolutionarily most homologous to BLM. A restoration of apoptotic levels in cells from WS, XPB or XPD patients was attained only by overexpression of the specific helicase. Our data suggest a limited redundancy in the pathways of these RecQ helicases in p53-induced apoptosis.
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Project description:While aneuploidy is found in more than 90% of solid tumors, it is unclear whether aneuploidy is the cause or the consequence of tumorigenesis. Different mouse models deficient in centrosomal or spindle checkpoint proteins that induce aneuploidy show either a promotion or a decrease in tumorigenesis depending on the tissues and the types of oncogenic stimuli. To investigate the effects of aneuploidy in skin development and tumorigenesis, we used Plk4 over-expression (Plk4OE) during epidermal development to assess centrosome amplification and aneuploidy. We found that PLK4OE in the developing epidermis induced centrosome amplification and multipolar divisions, consequently led to p53 stabilization and apoptosis of epidermal progenitors. This delayed epidermal stratification and induced lethal skin barrier defect in 50% of the mice. Plk4 transgene expression was shutdown postnatally in the surviving mice and PLK4OE mice never developed spontaneous skin tumors. Concomitant Plk4OE and P53 deletion (PLK4OE/p53cKO) rescued the defects in differentiation and stratification. Unexpectedly, p53 deletion did not rescue the apoptosis or eventual elimination of the cells overexpressing PLK4 and presenting multiple centrosomes. Remarkably, the short term presence of cells with supernumerary centrosomes postnatally was sufficient to generate aneuploidy and triggered spontaneous skin cancers with complete penetrance. These results reveal for the first time that aneuploidy induced by centrosome amplification, even if transient, can trigger tumorigenesis.
2015-10-27 | E-MTAB-3733 | biostudies-arrayexpress
Project description:Angiogenin, a 14-kDa multifunctional pro-angiogenic growth factor, is upregulated in several types of cancers. Anti-angiogenin monoclonal antibodies used as antagonists inhibited the establishment, progression and metastasis of human cancer cells in athymic mice (Olson et al., 1994). Silencing angiogenin and inhibition of angiogenin's nuclear translocation blocked cell survival and induced cell death in B-lymphoma and endothelial cells latently infected with Kaposi sarcoma-associated herpesvirus (Sadagopan et al., 2009), suggesting that actively proliferating cancer cells could be inducing angiogenin for inhibiting apoptotic pathways. However, the mechanism of cell survival and apoptosis regulation by angiogenin and their functional significance in cancer is not known. We demonstrate that angiogenin interacts with p53 and colocalizes in the nucleus. Silencing endogenous angiogenin induced p53 promoter activation and p53 target gene (p53, p21 and Bax) expression, downregulated anti-apoptotic Bcl-2 gene expression and increased p53-mediated cell death. In contrast, angiogenin expression blocked pro-apoptotic Bax and p21 expression, induced Bcl-2 and blocked cell death. Angiogenin also co-immunoprecipitated with p53 regulator protein Mdm2. Angiogenin expression resulted in the inhibition of p53 phosphorylation, increased p53-Mdm2 interaction, and consequently increased ubiquitination of p53. Taken together, these studies demonstrate that angiogenin promotes the inhibition of p53 function to mediate anti-apoptosis and cell survival. Our results reveal for the first time a novel p53 interacting function of angiogenin in anti-apoptosis and survival of cancer cells and suggest that targeting angiogenin could be an effective therapy for several cancers.
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Project description:Inositol pyrophosphates have been implicated in numerous biological processes. Inositol hexakisphosphate kinase-2 (IP6K2), which generates the inositol pyrophosphate, diphosphoinositol pentakisphosphate (IP7), influences apoptotic cell death. The tumor suppressor p53 responds to genotoxic stress by engaging a transcriptional program leading to cell-cycle arrest or apoptosis. We demonstrate that IP6K2 is required for p53-mediated apoptosis and modulates the outcome of the p53 response. Gene disruption of IP6K2 in colorectal cancer cells selectively impairs p53-mediated apoptosis, instead favoring cell-cycle arrest. IP6K2 acts by binding directly to p53 and decreasing expression of proarrest gene targets such as the cyclin-dependent kinase inhibitor p21.
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Project description:UnlabelledIn response to oncogene activation and oncogene-induced aberrant proliferation, mammalian cells activate apoptosis and senescence, usually via the p53-ARF tumor-suppressor pathway. Apoptosis is a known barrier to cancer and is usually downregulated before full malignancy, but senescence as an anticancer barrier is controversial due to its presence in the tumor environment. In addition, senescence may aid cancer progression via releasing senescence-associated factors that instigate neighboring tumor cells. Here, it is demonstrated that apoptosis unexpectedly remains robust in ErbB2 (ERBB2/HER2)-initiated mammary early lesions arising in adult mice null for either p53 or ARF. These early lesions, however, downregulate senescence significantly. This diminished senescence response is associated with accelerated progression to cancer in ARF-null mice compared with ARF-wild-type mice. Thus, the ARF-p53 pathway is dispensable for the apoptosis anticancer barrier in the initiation of ErbB2 breast cancer, the apoptosis barrier alone cannot halt mammary tumorigenesis, and senescence is a key barrier against carcinogenesis.ImplicationsFindings in this relevant mouse model of HER2-driven breast cancer suggest that effective prevention relies upon preserving both ARF/p53-independent apoptosis and ARF/p53-dependent senescence.
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Project description:The WRN DNA helicase is a member of the DExH-containing DNA helicase superfamily that includes XPB, XPD, and BLM. Mutations in WRN are found in patients with the premature aging and cancer susceptibility syndrome known as Werner syndrome (WS). p53 binds to the WRN protein in vivo and in vitro through its carboxyl terminus. WS fibroblasts have an attenuated p53- mediated apoptotic response, and this deficiency can be rescued by expression of wild-type WRN. These data support the hypothesis that p53 can induce apoptosis through the modulation of specific DExH-containing DNA helicases and may have implications for the cancer predisposition observed in WS patients.
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