Inhibitory member of the apoptosis-stimulating protein of p53 is overexpressed in bladder cancer and correlated to its progression

Wu, Zhi‐Ying; Wang, Sugui; Xue, Peng; Wang, Shoulin; Wang, Gongcheng; Zhang, Wei

doi:10.1097/md.0000000000006640

Cited by 3 publications

(3 citation statements)

References 28 publications

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“…Indeed, there is growing evidence that overexpression, rather than mutation, of iASPP conveys its oncogenic properties. In addition to our previous characterization in p53 wild-type breast cancer (32), elevated iASPP levels have recently been reported in multiple human cancers, including bladder cancer (63), non-small-cell lung cancer (64), ovarian clear cell carcinoma (65), colorectal cancer (66), and particularly in acute leukemia where p53 mutations are relatively rare (67, 68).…”

Section: Discussionmentioning

confidence: 65%

iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

Chen

Zhong

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The most frequently mutated protein in human cancer is p53, a transcription factor (TF) that regulates myriad genes instrumental in diverse cellular outcomes including growth arrest and cell death. Cell context-dependent p53 modulation is critical for this life-or-death balance, yet remains incompletely understood. Here we identify sequence signatures enriched in genomic p53-binding sites modulated by the transcription cofactor iASPP. Moreover, our p53–iASPP crystal structure reveals that iASPP displaces the p53 L1 loop—which mediates sequence-specific interactions with the signature-corresponding base—without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. A TF commonly uses multiple structural modules to recognize its cognate DNA, and thus this mechanism of a cofactor fine-tuning TF–DNA interactions through targeting a particular module is likely widespread. Previously, all tumor suppressors and oncoproteins that associate with the p53 DNA-binding domain—except the oncogenic E6 from human papillomaviruses (HPVs)—structurally cluster at the DNA-binding site of p53, complicating drug design. By contrast, iASPP inhibits p53 through a distinct surface overlapping the E6 footprint, opening prospects for p53-targeting precision medicine to improve cancer therapy.

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Section: Discussionmentioning

confidence: 65%

iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

Chen

Zhong

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…It reduced damaged cell death and accumulated injuries in cells, which was beneficial for tumour survival. According to our results, low ASPP2 expression independently predicted poor prognosis of ESCC patients, which is consistent with previous reports of other cancers [22,23]. The results of qRT-PCR in this study demonstrated that the relative expression of ASPP2 mRNA was markedly downregulated in ESCC samples compared with the paired tumor adjacent tissues.…”

Section: Discussionmentioning

confidence: 99%

Expression and significance of ASPP2 in squamous carcinoma of esophagus

Liu

et al. 2018

The Kaohsiung J of Med Scie

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To study the significance of apoptosis stimulating protein of P53 2 (ASPP2) expression in esophageal squamous cell carcinoma (ESCC), immunohistochemistry S-P method was used to examine the expression of ASPP2 in 136 cases of ESCC, 35 cases of high grade intraepithelial neoplasia (HGIN), 29 cases of low grade intraepithelial neoplasia (LGIN) and 37 cases of normal esophageal epithelium (NEE). The associations of ASPP2 expression with clinicopathological data and overall survival (OS) were also analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate ASPP2 expression in a total of 20 matched human ESCC tumor tissues and normal adjacent tissues (NAT). In addition, EC109 cells were treated with cisplatin (CDDP) in vitro for 24 h (the intervention group) and the control group was set up at the same time. Western blot was used to examine the expression of ASPP2 protein between the two groups. The expression of ASPP2 decreased progressively from NEE to LGIN, to HGIN, and to ESCC, and it was related to TNM stage, histological differentiation and lymph node metastasis in ESCC (P < 0.05). ASPP2 was a protective factor of patients with ESCC (P = 0.008). The relative expression of ASPP2 mRNA was markedly downregulated in ESCC compared with the paired NAT (P < 0.01). Western blot results showed that cells in the intervention group could express ASPP2 while there was no expression of ASPP2 in the control group. Taken together, these results indicate that the abnormal expression of ASPP2 may play an important role for development and metastasis in ESCC.

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“…RNA-seq and p53 ChIP-seq analyses have confirmed that many iASPP/p53 coregulated targets are involved in regulating apoptosis, consistent with iASPP as an evolutionarily conserved inhibitor of p53-mediated apoptosis [ 6 , 7 ]. Evidence to date suggests that iASPP is an oncoprotein, as high expression of iASPP associates with poor prognosis in ovarian, melanoma, prostate, glioma and bladder cancers [ 8 – 12 ]. In vitro and xenograft studies have shown that iASPP has pro-proliferative and chemoresistant properties.…”

Section: Introductionmentioning

confidence: 99%

p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer

et al. 2023

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Oncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor of p53, as a paradoxical suppressor of inflammation and oncogenic KRASG12D-driven PC tumorigenesis. iASPP suppresses PC onset driven by KRASG12D alone or KRASG12D in combination with mutant p53R172H. iASPP deletion limits acinar-to-ductal metaplasia (ADM) in vitro but accelerates inflammation and KRASG12D-induced ADM, pancreatitis and PC tumorigenesis in vivo. KRASG12D/iASPPΔ8/Δ8 tumours are well-differentiated classical PCs and their derivative cell lines form subcutaneous tumours in syngeneic and nude mice. Transcriptomically, either iASPP deletion or p53 mutation in the KRASG12D background altered the expression of an extensively overlapping gene set, comprised primarily of NF-κB and AP1-regulated inflammatory genes. All these identify iASPP as a suppressor of inflammation and a p53-independent oncosuppressor of PC tumorigenesis.

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Inhibitory member of the apoptosis-stimulating protein of p53 is overexpressed in bladder cancer and correlated to its progression

Abstract: Supplemental Digital Content is available in the text

Cited by 3 publications

References 28 publications

iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

Expression and significance of ASPP2 in squamous carcinoma of esophagus

p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer

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