Estrogen receptor prevents p53-dependent apoptosis in breast cancer

Bailey, Scott; Shin, Hyunjin; Westerling, Thomas; Liu, Xiaole Shirley; Brown, Myles

doi:10.1073/pnas.1018858109

Cited by 132 publications

(145 citation statements)

References 57 publications

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“…Similarly, in human breast cancer cells, estrogen downregulates the P53 target genes, including ATF3, BGT2 and TRAF4, which are involved in P53-mediated apoptosis (Bailey et al, 2012). We found that at 33-34 dpf, btg2 mRNA was downregulated while traf4a mRNA had similar levels of expression in zar1 mutant ovaries and control sibling ovaries (Fig.…”

Section: Estrogen Treatment Restores Oogenesis In Zar1 Mutantssupporting

confidence: 58%

Translation repression by maternal RNA binding protein zar1 is essential for early oogenesis in zebrafish

et al. 2016

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A large amount of maternal RNA is deposited in oocytes and is reserved for later development. Control of maternal RNA translation during oocyte maturation has been extensively investigated and its regulatory mechanisms are well documented. However, translational regulation of maternal RNA in early oogenesis is largely unexplored. In this study, we generated zebrafish zar1 mutants that result in early oocyte apoptosis and fully penetrant male development. Loss of p53 suppresses the apoptosis in zar1 mutants and restores oocyte development. zar1 immature ovaries show upregulation of proteins implicated in endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). More importantly, loss of Zar1 causes marked upregulation of zona pellucida (ZP) family proteins, while overexpression of ZP proteins in oocytes causes upregulation of stress-related activating transcription factor 3 (atf3), arguing that tightly controlled translation of ZP proteins is essential for ER homeostasis during early oogenesis. Furthermore, Zar1 binds to ZP gene mRNAs and represses their translation. Together, our results indicate that regulation of translational repression and de-repression are essential for precisely controlling protein expression during early oogenesis.

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Section: Estrogen Treatment Restores Oogenesis In Zar1 Mutantssupporting

confidence: 58%

Translation repression by maternal RNA binding protein zar1 is essential for early oogenesis in zebrafish

et al. 2016

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“…In tumors with wild-type p53, p53 responses can be inhibited by downregulating p53 activity or its effectors' activity. For instance, in estrogen receptor-positive (ER þ ) breast cancers, ER prevents the p53-mediated apoptotic response by directly interacting with p53 (6).…”

Section: Traditional Tumor Suppressor Functions Of P53mentioning

confidence: 99%

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

2015

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The tumor suppressor p53 has established functions in cancer. Specifically, it has been shown to cause cell-cycle arrest and apoptosis in response to DNA damage. It is also one of the most commonly mutated or silenced genes in cancer and for this reason has been extensively studied. Recently, the role of p53 has been shown to go beyond its effects on cell cycle and apoptosis, with effects on metabolism emerging as a key contributor to cancer growth in situations where p53 is lost. Beyond this, the role of p53 in the tumor microenvironment is poorly understood. The publication by Wang and colleagues demonstrates for the first time that p53 is a key negative regulator of aromatase and, hence, estrogen production in the breast tumor microenvironment. It goes further by demonstrating that an important regulator of aromatase, the obesity-associated and tumor-derived factor prostaglandin E 2 , inhibits p53 in the breast adipose stroma. This review presents these findings in the context of established and emerging roles of p53 and discusses possible implications for the treatment of breast cancer. Cancer Res; 75(23); 5001-7. Ó2015 AACR.

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“…56,57 The regulation of cell death by the p53 protein is quite complex, acting both at the level of autophagy, 58 lysosomes, 59 or at the core machinery of programmed cell death. [60][61][62][63][64][65] In addition to DNA damage response and cell death, p53 plays a crucial role in regulating cellular senescence [66][67][68] by interacting, for example, with MageA2, 69 PATZ1, 70 4E-BP1, 71 mTOR, 72,73 highlighting the vast complexity of this crucial regulation.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics of the full-length p53 monomer

Chillemi¹,

Davidovich

D’Abramo³

et al. 2013

Cell Cycle

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The p53 protein is frequently mutated in a very large proportion of human tumors, where it seems to acquire gain-of-function activity that facilitates tumor onset and progression. A possible mechanism is the ability of mutant p53 proteins to physically interact with other proteins, including members of the same family, namely p63 and p73, inactivating their function. Assuming that this interaction might occurs at the level of the monomer, to investigate the molecular basis for this interaction, here, we sample the structural flexibility of the wild-type p53 monomeric protein. The results show a strong stability up to 850 ns in the DNA binding domain, with major flexibility in the N-terminal transactivations domains (TAD1 and TAD2) as well as in the C-terminal region (tetramerization domain). Several stable hydrogen bonds have been detected between N-terminal or C-terminal and DNA binding domain, and also between N-terminal and C-terminal. Essential dynamics analysis highlights strongly correlated movements involving TAD1 and the proline-rich region in the N-terminal domain, the tetramerization region in the C-terminal domain; Lys120 in the DNA binding region. The herein presented model is a starting point for further investigation of the whole protein tetramer as well as of its mutants

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Estrogen receptor prevents p53-dependent apoptosis in breast cancer

Cited by 132 publications

References 57 publications

Translation repression by maternal RNA binding protein zar1 is essential for early oogenesis in zebrafish

Translation repression by maternal RNA binding protein zar1 is essential for early oogenesis in zebrafish

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

Molecular dynamics of the full-length p53 monomer

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