TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

Amelio, Ivano; Inoue, Satoshi; Markert, Elke; Levine, Arnold J.; Knight, Richard; Mak, Tak W.; Melino, Gerry

doi:10.1073/pnas.1410609111

Cited by 99 publications

(105 citation statements)

References 29 publications

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“…Transient overexpression of TAp73 leads to pro-angiogenesis. In contrast, long-term induction of TAp73 leads to angiogenic suppression (26). Similarly, we also found TAp73 could inhibit the ability of tube formation in human umbilical vein endothelial cells (HUVEC) when HUVEC co-cultured with H1299 LAC cells with TAp73 stable overexpressed not for transient transfection (data not shown).…”

Section: Discussionmentioning

confidence: 59%

Association between TAp73, p53 and VASH1 expression in lung adenocarcinoma

Zhang

et al. 2018

Oncol Lett

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Abstract. TAp73 and p53 are involved in regulating tumor angiogenesis and vasohibin-1 (VASH1) is an anti-angiogenic factor. Whether TAp73 regulates angiogenesis positively or negatively is controversial. The status of P53 may determine the effect of TAp73 on angiogenesis. To the best of our knowledge it has not been previously reported whether TAp73, p53 and VASH1 are coexpressed in lung cancer. We profiled the association between TAp73 and p53 and VASH1 expression in lung adenocarcinoma (LAC) and investigated the function of TAp73 in regulating tumor angiogenesis. TAp73, p53 and VASH1 expression in 53 human LAC tissues and the adjacent normal tissues were evaluated using immunohistochemistry. The positive expression rates of p53, TAp73 and VASH1 were significantly higher (92.6, 97.7 and 67.4%, respectively) in LAC tissue compared with paraneoplastic lung tissue (7.4, 2.3 and 32.6%, respectively, P<0.01). Pearson's correlation coefficient showed a significant positive correlation between p53 and TAp73 (r= 0.474, P<0.01) and TAp73α and VASH1 (r= 0.367, P<0.01). The positive expression rate of p53 and VASH1 was almost significantly correlated (r= 0.187, P= 0.055). Similarly, p53 expression intensity had a significant positive correlation with TAp73α (r= 0.517, P<0.01) and with VASH1 (r= 0.277, P<0.01), as did TAp73α with VASH1 (r=0.351, P<0.01). TAp73, p53 (mutant) and VASH1 expression was significantly higher in LAC tissue compared with paraneoplastic lung tissue. The expression trends of the three proteins were significantly positively correlated with each other in LAC. These results suggest that TAp73 may suppress tumor angiogenesis in LAC.

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Section: Discussionmentioning

confidence: 59%

Association between TAp73, p53 and VASH1 expression in lung adenocarcinoma

Zhang

et al. 2018

Oncol Lett

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“…For example, the involvement of the prolyl hydroxylase (PHD) enzyme, which induce hydroxylation of proline residues under normoxia, as well as the von Hippel-Lindau (VHL) protein, which recognize hydroxylated prolines and induce the poly-ubiquitination to mediate proteasomal HIF degradation, need to be analyzed for a full overview of the pathway 29,30 . Moreover, ubiquitous detection of HIFs would also determine the protein stability and degradation that can be alter 31,32 . Furthermore, proliferation by Ki67 and apoptosis by TUNEL staining are determined in vivo through staining of AT histological sections.…”

Section: Representative Resultsmentioning

confidence: 99%

Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis

Bözec

Hannemann

2016

JoVE

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Considering that adipose tissue (AT) is an endocrine organ, it can influence whole body metabolism. Excessive energy storage leads to the dysregulation of adipocytes, which in turn induces abnormal secretion of adipokines, triggering metabolic syndromes such as obesity, dyslipidemia, hyperglycemia, hyperinsulinemia, insulin resistance and type 2 diabetes. Therefore, investigating the molecular mechanisms behind adipocyte dysregulation could help to develop novel therapeutic strategies. Our protocol describes methods for evaluating the molecular mechanism affected by hypoxic conditions of the AT, which correlates with adipocyte apoptosis in adult mice. This protocol describes how to analyze AT in vivo through gene expression profiling as well as histological analysis of adipocyte differentiation, proliferation and apoptosis during hypoxia exposure, ascertained through staining of hypoxic cells or HIF-1α protein. Furthermore, in vitro analysis of adipocyte differentiation and its responses to various stimuli completes the characterization of the molecular pathways behind possible adipocyte dysfunction leading to metabolic syndromes.

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“…We demonstrated that the p53-like responsive element in the BNIP3 promoter, previously experimentally validated for p53 can also be recognized by TAp73. As BNIP3 is a HIF1a target gene, 90 and HIF1a is repressed by TAp73, 41 relationship between TAp73 and BNIP3 can also depend on an indirect regulation via HIF1.…”

Section: Discussionmentioning

confidence: 99%

“…TAp73 indeed directly binds HIF-1a protein, promoting its oxygen-independent degradation. 41,42 Conversely, DNp73 antagonizes TAp73 and it is considered an oncogenic protein. [43][44][45][46] It can form inactive complexes with TAp73, and also bind common promoters with p53 and TAp73, thus inhibiting their transcriptional activity.…”

Section: Introductionmentioning

confidence: 99%

TAp73 transcriptionally represses BNIP3 expression

et al. 2015

Self Cite

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TAp73 is a tumor suppressor transcriptional factor, belonging to p53 family. Alteration of TAp73 in tumors might lead to reduced DNA damage response, cell cycle arrest and apoptosis. Carcinogen-induced TAp73 ¡/¡ tumors display also increased angiogenesis, associated to hyperactivition of hypoxia inducible factor signaling. Here, we show that TAp73 suppresses BNIP3 expression, directly binding its gene promoter. BNIP3 is a hypoxia responsive protein, involved in a variety of cellular processes, such as autophagy, mitophagy, apoptosis and necrotic-like cell death. Therefore, through different cellular process altered expression of BNIP3 may differently contribute to cancer development and progression. We found a significant upregulation of BNIP3 in human lung cancer datasets, and we identified a direct association between BNIP3 expression and survival rate of lung cancer patients. Our data therefore provide a novel transcriptional target of TAp73, associated to its antagonistic role on HIF signaling in cancer, which might play a role in tumor suppression.

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TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

Cited by 99 publications

References 29 publications

Association between TAp73, p53 and VASH1 expression in lung adenocarcinoma

Association between TAp73, p53 and VASH1 expression in lung adenocarcinoma

Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis

TAp73 transcriptionally represses BNIP3 expression

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