Caspase-1 is a novel target of p63 in tumor suppression

Celardo, Ivana; Grespi, Francesca; Antonov, Alexey V.; Bernassola, Francesca; Garabadgiu, A. V.; Melino, Gerry; Amelio, Ivano

doi:10.1038/cddis.2013.175

Cited by 46 publications

(32 citation statements)

References 57 publications

(66 reference statements)

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“…The analysis of the K-M estimation curves was performed as previously described. [86][87] Briefly, the samples were divided in two cohorts to maximize the positive correlation between the matrix metalloproteinase 7 and transforming growth factor b1 expression profiles. The separation of patients into 'cohort 1' and 'cohort 2' along with the survival information was next used to identify any significant differences in the survival outcome.…”

Section: Bioinformatic Analysismentioning

confidence: 99%

ΔNp63 targets cytoglobin to inhibit oxidative stress-induced apoptosis in keratinocytes and lung cancer

et al. 2015

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During physiological aerobic metabolism, the epidermis undergoes significant oxidative stress as a result of the production of reactive oxygen species (ROS). To maintain a balanced oxidative state, cells have developed protective antioxidant systems, and preliminary studies suggest that the transcriptional factor p63 is involved in cellular oxidative defence. Supporting this hypothesis, the ΔNp63α isoform of p63 is expressed at high levels in the proliferative basal layer of the epidermis. Here we identify the CYGB gene as a novel transcriptional target of ΔNp63 that is involved in maintaining epidermal oxidative defence. The CYGB gene encodes cytoglobin, a member of the globin protein family, which facilitates the diffusion of oxygen through tissues and acts as a scavenger for nitric oxide or other ROS. By performing promoter activity assays and chromatin immunoprecipitation, reverse transcriptase quantitative PCR and western blotting analyses, we confirm the direct regulation of CYGB by ΔNp63α. We also demonstrate that CYGB has a protective role in proliferating keratinocytes grown under normal conditions, as well as in cells treated with exogenous hydrogen peroxide. These results indicate that ΔNp63, through its target CYGB has an important role in the cellular antioxidant system and protects keratinocytes from oxidative stress-induced apoptosis. The ΔNp63-CYGB axis is also present in lung and breast cancer cell lines, indicating that CYGB-mediated ROS-scavenging activity may also have a role in epithelial tumours. In human lung cancer data sets, the p63-CYGB interaction significantly predicts reduction of patient survival.

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Section: Bioinformatic Analysismentioning

confidence: 99%

ΔNp63 targets cytoglobin to inhibit oxidative stress-induced apoptosis in keratinocytes and lung cancer

et al. 2015

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“…Cyclin E transcription start site TP73 transcription start site Computing, Vienna, Austria) was used to perform statistical tests and to derive the P-value (for full details of the procedure, see Celardo et al 55 Two different lung cancer data sets of patients with a strong positive correlation between Set7/9 and TP73 showed poor survival outcome compared with the cohort where Set7/9 and TP73 exhibited a strong negative correlation ( Figure 5). Similar results were obtained for breast cancer patients ( Figure 5; Supplementary Data).…”

Section: Chip Assay Chip Assaymentioning

confidence: 99%

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress

et al. 2014

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During the recent years lysine methyltransferase Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) has emerged as an important regulator of different transcription factors. In this study, we report a novel function for Set7/9 as a critical co-activator of E2 promoter-binding factor 1 (E2F1)-dependent transcription in response to DNA damage. By means of various biochemical, cell biology, and bioinformatics approaches, we uncovered that cell-cycle progression through the G1/S checkpoint of tumour cells upon DNA damage is defined by the threshold of expression of both E2F1 and Set7/9. The latter affects the activity of E2F1 by indirectly modulating histone modifications in the promoters of E2F1-dependent genes. Moreover, Set7/9 differentially affects E2F1 transcription targets: it promotes cell proliferation via expression of the CCNE1 gene and represses apoptosis by inhibiting the TP73 gene. Our biochemical screening of the panel of lung tumour cell lines suggests that these two factors are critically important for transcriptional upregulation of the CCNE1 gene product and hence successful progression through cell cycle. These findings identify Set7/9 as a potential biomarker in tumour cells with overexpressed E2F1 activity. Cell Death and Differentiation (2014) 21, 1889-1899; doi:10.1038/cdd.2014.108; published online 15 August 2014Lysine methylation of non-histone proteins has recently emerged as a novel regulatory mechanism to control protein functions. 1-4Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) is a founding member of the family of non-chromatin lysine methyltransferases (KMTases). Set7/9 was initially identified as a monomethylase of histone H3 lysine 4 (H3K4) in vitro. 4,5However, we and others showed that the recombinant Set7/9 failed to target nucleosomes for methylation, [6][7][8] suggesting that Set7/9 functions as a factor-specific KMTase. There have been several non-histone proteins reported as the substrates for Set7/9, including TAF10 (TATA box binding protein (TBP)-associated factor, 30 kDa), 9 oestrogen receptor a (ERa), 10 RelA, 11 PCAF (P300/CBP-associated factor), 12 Stat3,13 Yap, 14 and Suv39h1. 15 However, in most cases the functional significance of this methylation is still not clear. The beststudied targets of Set7/9-mediated methylation are p53 16 and E2 promoter-binding factor 1 (E2F1), 17 transcription factors involved in regulation of DNA damage response (DDR).In response to genotoxic stress cancer cells undergo cell-cycle arrest either in G1/S or G2/M or in both checkpoints. The presence of intact p53 in cancer cells mediates transient G1/S checkpoint arrest, 18,19 which allows cells to repair the damaged DNA before replication or, if the amount of damage is insurmountable, drives cells into apoptosis. 20,21On the contrary, the activity of the E2F family transcription factors, especially E2F1, drives cells from the G1/S block to mitosis. 22,23 Transcriptional activity of E2F1, in turn, is repressed by the retin...

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“…These include common roles in the protection of the reproductive system [150-152], in development [153-159], aging [160, 161], cell death [162-164], cancer [159, 165-167], redox regulation [161, 168, 169], and metabolism [168, 170, 171]. Moreover, as is the case for p53 [172, 173], p63 is an important factor in cancer response to therapy as p63 and p53 are found in similar molecular complexes that mediate cisplatin resistance [174].…”

Section: Introductionmentioning

confidence: 99%

Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities

et al. 2014

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The ubiquitin proteasome system (UPS) plays a role in the regulation of most cellular pathways, and its deregulation has been implicated in a wide range of human pathologies that include cancer, neurodegenerative and immunological disorders and viral infections. Targeting the UPS by small molecular regulators thus provides an opportunity for the development of therapeutics for the treatment of several diseases. The proteasome inhibitor Bortezomib was approved for treatment of hematologic malignancies by the FDA in 2003, becoming the first drug targeting the ubiquitin proteasome system in the clinic. Development of drugs targeting specific components of the ubiquitin proteasome system, however, has lagged behind, mainly due to the complexity of the ubiquitination reaction and its outcomes. However, significant advances have been made in recent years in understanding the molecular nature of the ubiquitination system and the vast variety of cellular signals that it produces. Additionally, improvement of screening methods, both in vitro and in silico, have led to the discovery of a number of compounds targeting components of the ubiquitin proteasome system, and some of these have now entered clinical trials. Here, we discuss the current state of drug discovery targeting E3 ligases and the opportunities and challenges that it provides.

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Caspase-1 is a novel target of p63 in tumor suppression

Cited by 46 publications

References 57 publications

ΔNp63 targets cytoglobin to inhibit oxidative stress-induced apoptosis in keratinocytes and lung cancer

ΔNp63 targets cytoglobin to inhibit oxidative stress-induced apoptosis in keratinocytes and lung cancer

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress

Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities

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