Updates on p53: modulation of p53 degradation as a therapeutic approach

Dey, Anwesha; Verma, Chandra; Lane, David P.

doi:10.1038/sj.bjc.6604098

Cited by 61 publications

(48 citation statements)

References 34 publications

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“…A prominent example is the tumor suppressor p53, a transcription factor whose stability is regulated by multiple proteins including several ubiquitin ligases (Lavin and Gueven 2006). Modulation of p53 degradation is now becoming a promising therapeutic approach (Dey et al 2008). Thus, future studies directed at the stability control of the TEA domain regulator Tec1 in S. cerevisiae may contribute to a more precise understanding of the molecular mechanisms underlying the complex regulation of transcription factors during cellular development.…”

Section: Discussionmentioning

confidence: 99%

The TEA Transcription Factor Tec1 Links TOR and MAPK Pathways to Coordinate Yeast Development

et al. 2011

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In Saccharomyces cerevisiae, the TEA transcription factor Tec1 controls several developmental programs in response to nutrients and pheromones. Tec1 is targeted by the pheromone-responsive Fus3/Kss1 mitogen-activated protein kinase (MAPK) cascade, which destabilizes the transcription factor to ensure efficient mating of sexual partner cells. The regulation of Tec1 by signaling pathways that control cell division and development in response to nutrients, however, is not known. Here, we show that Tec1 protein stability is under control of the nutrient-sensitive target of rapamycin complex 1 (TORC1) signaling pathway via the Tip41-Tap42-Sit4 branch. We further show that degradation of Tec1 upon inhibition of TORC1 by rapamycin does not involve polyubiquitylation and appears to be proteasome independent. However, rapamycin-induced Tec1 degradation depends on the HECT ubiquitin ligase Rsp5, which physically interacts with Tec1 via conserved PxY motives. We further demonstrate that rapamycin and mating pheromone control Tec1 protein stability through distinct mechanisms by targeting different domains of the transcription factor. Finally, we show that Tec1 is a positive regulator of yeast chronological lifespan (CLS), a known TORC1-regulated process. Our findings indicate that in yeast, Tec1 links TORC1 and MAPK signaling pathways to coordinate control of cellular development in response to different stimuli.

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Section: Discussionmentioning

confidence: 99%

The TEA Transcription Factor Tec1 Links TOR and MAPK Pathways to Coordinate Yeast Development

et al. 2011

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“…and could significantly contribute to carcinogenesis. 30 A decrease in the expression of signaling molecules in MCF-7/TOB cells may be due to TOB's ability to modulate and inactivate gene expression via deadenylation, facilitating its antiproliferative effects.…”

Section: Discussionmentioning

confidence: 99%

TOB suppresses breast cancer tumorigenesis

O’Malley

Zhang

et al. 2009

Intl Journal of Cancer

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Transducer of ErbB-2 (TOB) is a member of the TOB/Btg gene family. A role for TOB in the suppression of human tumorigenesis has been proposed, based on the observations that TOB-knockout mice spontaneously form tumors and TOB expression is lost in human lung and thyroid cancers. However, the role of TOB in human breast cancer remains unknown. To evaluate the this role, we screened a panel of breast cancer cell lines for TOB expression levels and found that they are inversely correlated with the tumorigenicity and metastatic potential of the cell lines. In addition, we demonstrated for the first time that TOB expression is inversely correlated with breast cancer progression in clinical specimens. These results strongly indicate that the loss of TOB expression plays a role in breast cancer progression. We have also provided the first evidence that TOB functions as a tumor suppressor in breast cancer MCF-7 cells, using gain-of-function and loss-offunction approaches to manipulate TOB expression. Cell-cycle analysis further revealed that TOB can prolong the G1-S phase transition by inducing arrest at G1-S phase. Moreover, upregulation of the cyclin-dependent kinase inhibitor p27 and downregulation of the antiapoptotic proteins Bcl-2 and Bcl-XL were observed in MCF7/TOB transfectants. Conversely, opposite results were observed in shRNA-TOB transfectants. Furthermore, decreased activity of Erk2, AKT, CrkL, PDK1, and Smads were observed in TOB-overexpressing cells. Taken together, these data provide evidence that TOB can function as a tumor suppressor in breast cancer through modulation and regulation of multiple signaling pathways. ' UICCKey words: TOB; ErbB-2; tumor suppressor Cell growth and differentiation in normal tissues are controlled by a balance of 2 opposing signaling pathways, namely positive and negative signaling. A Transducer of ErbB-2 (TOB), known as TOB/TOB1, is ubiquitously expressed in human adult tissues and was first identified by screening an expression library that detected protein-protein interactions with an ErbB2 probe. 1 The TOB gene is located on chromosome 17q21, telomeric to the BRCA1 locus. TOB is a 45-kDa protein belonging to the TOB/BTG family, which includes proteins, such as PC3/TIS21/BTG2, BTG1, TOB2, ANA, BTG3, PC3K and others. These proteins share a highly conserved amino-terminal region known as the Btg homology domain.Overexpression of TOB/BTG family proteins negatively regulates the cell cycle by inhibiting G1 progression. 1,2-7 Conversely, the antiproliferative activity of TOB is impaired in the presence of exogenously coexpressed Cyclin D1. 7 TOB's antiproliferative activity is regulated through phosphorylation and nuclear localization. In its active state, TOB is unphosphorylated and it is inactivated by phosphorylation. Growth factor stimulation of the RTK/Ras/MAPK pathway results in rapid phosphorylation of these sites by Erk1and Erk2. 8 TOB is also phosphorylated via the Akt pathway by the serine/threonine kinase p90rsk1. 9 In addition, the antiproliferative activity of ...

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“…[48][49][50][51][52] (3) Ionizing radiation also causes DNA damage. (5) Chk2 is activated by ATM, and its activation involves dimerization and autophosphorylation. 54,55 (6) ATM phosphorylates p53.…”

Section: Modelmentioning

confidence: 99%

“…As p53 plays a critical role in preventing cells from becoming cancerous, extensive studies have been made to control the activity and stability of p53 for therapeutic purposes, such as in the treatment of cancers. [3][4][5][6] The level and transcriptional activity of p53 are controlled by the negative regulator Mdm2 (murine double minute 2). The E3 ligase protein Mdm2 directly binds to p53 and inhibits its transcriptional activity, favoring its nuclear export and causing its ubiquitinization and proteasomal degradation.…”

Section: Introductionmentioning

confidence: 99%