DEC1, a Basic Helix-Loop-Helix Transcription Factor and a Novel Target Gene of the p53 Family, Mediates p53-dependent Premature Senescence

Qian, Yingjuan; Zhang, Jin; Yan, Bingfang; Chen, Xinbin

doi:10.1074/jbc.m708624200

Cited by 107 publications

(119 citation statements)

References 46 publications

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“…We previously showed that DEC1, a target of p53, mediates G1 arrest and premature senescence in p53-and p21-independent manners (16). In this study, we showed that DEC1 inhibits DNA damage-induced apoptosis in a p53-dependent manner.…”

Section: Discussionsupporting

confidence: 51%

“…DEC1 is defined as a senescence marker because it is up-regulated in premalignant tumors (15). Consistent with this, our previous studies showed that DEC1 is a target of the p53 family and mediates G1 cell cycle arrest and DNA damage-induced premature senescence (16,17). Evidence also showed that DEC1 plays a role in cell death.…”

supporting

confidence: 64%

“…S4A), and two MCF7 cell clones (6 and 16; Fig. S4 B and C), all of which can inducibly express DEC1 under the control of a tetracycline-regulated promoter (16). Conversely, we showed that upon DEC1-KD, both the basal and DNA damage-induced levels of MIC-1 were markedly increased in RKO and MCF7 cells (Fig.…”

Section: Dec1mentioning

confidence: 77%

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Differentiated embryo-chondrocyte expressed gene 1 regulates p53-dependent cell survival versus cell death through macrophage inhibitory cytokine-1

Qian

Jung

Chen

2012

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

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Activation of p53 upon DNA damage induces an array of target genes, leading to cell cycle arrest and/or apoptosis. However, the mechanism by which the cell fate is controlled by p53 remains to be clarified. Previously, we showed that DEC1, a basic helix-loophelix transcription factor and a target of p53, is capable of inducing cell cycle arrest and mediating DNA damage-induced premature senescence. Here, we found that ectopic expression of DEC1 inhibits, whereas knockdown of DEC1 enhances, DNA damage-induced cell death. Surprisingly, we showed that the anti-cell-death activity of DEC1 is p53 dependent, but DEC1 does not directly modulate p53 expression. Instead, we showed that DEC1 inhibits the ability of p53 to induce macrophage inhibitory cytokine-1 (MIC-1), but not other prosurvival/proapoptotic targets, including p21 and Puma. Importantly, we showed that upon binding to their respective response elements on the MIC-1 promoter, DEC1 and p53 physically interact on the MIC-1 promoter via the basic helix-loop-helix domain in DEC1 and the tetramerization domain in p53, which likely weakens the DNA-binding activity of p53 to the MIC-1 promoter. Finally, we found that depletion of MIC-1 abrogates the ability of DEC1 to attenuate DNA damage-induced cell death. Together, we hypothesize that DEC1 controls the response of p53-dependent cell survival vs. cell death to a stress signal through MIC-1.Stimulated by retinoic acid 13 | growth differentiation factor 15 I n response to genotoxic stress, p53 is activated, leading to induction of cell death regulators, such as Puma, Bax, FDXR, and PolH, and cell survival regulators, such as p21, Mdm2, 14-3-3σ, and GADD45 (1-3). However, a central puzzle is how p53 determines the cell fate in response to a specific stimulus. Previously, we and others have shown that the expression level and functional domains of p53 are involved in the cell fate determination (4-7) as well as several cofactors that alter the ability of p53 to transcriptionally regulate its targets. For examples, the ASPP family proteins (8), p53β (9), and p90 (10) preferentially affect p53 to regulate proapoptotic targets, such as Bax, but not p21. Conversely, BRCA1 (11) and HZF (12) cooperate with p53 to transactivate p21 but not Bax. Interestingly, hCAS/CSE1L is able to selectively affect a set of p53 targets and p53-dependent apoptosis without directly binding to p53 (13).DEC1 belongs to a subfamily of basic helix-loop-helix (bHLH) transcription factors and is a critical regulator of the circadian rhythm (14). DEC1 is defined as a senescence marker because it is up-regulated in premalignant tumors (15). Consistent with this, our previous studies showed that DEC1 is a target of the p53 family and mediates G1 cell cycle arrest and DNA damage-induced premature senescence (16,17). Evidence also showed that DEC1 plays a role in cell death. For examples, overexpression of DEC1 inhibits serum starvation-induced apoptosis in HEK293 cells (18), and DEC1 mediates TGF-β-induced cell survival in breast cancer cells (19). H...

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Section: Discussionsupporting

confidence: 51%

supporting

confidence: 64%

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Differentiated embryo-chondrocyte expressed gene 1 regulates p53-dependent cell survival versus cell death through macrophage inhibitory cytokine-1

Qian

Jung

Chen

2012

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

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“…Cells seeded on a six-well plate were uninduced or induced to express RNPC1a for 6 days. The senescence assay was performed as described previously (28).…”

Section: Methodsmentioning

confidence: 99%

p73 Expression Is Regulated by RNPC1, a Target of the p53 Family, via mRNA Stability

Yan

Zhang

et al. 2012

Molecular and Cellular Biology

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p73, a p53 family tumor suppressor, is expressed as TA and ⌬N isoforms. Due to the role of p73 in tumor suppression and neural development, its expression and activity are tightly regulated by multiple mechanisms, including transcription and posttranslational modifications. Here, we found that p73 mRNA stability is regulated by RNPC1, an RNA binding protein and a target of the p53 family. We also showed that a CU-rich element in the 3= untranslated region of p73 is recognized by and responsive to RNPC1. To explore the physiological significance of RNPC1-regulated p73 expression, we showed that the loss of RNPC1 in p53-null mouse embryonic fibroblasts leads to reduced expression of p73, along with decreased expression of p21, p130, and ␥-H2A.X, and consequently a decreased number of senescent cells. Furthermore, we observed that knockdown of TAp73 or p21, another target of RNPC1, attenuates the inhibitory effect of RNPC1 on cell proliferation and premature senescence, whereas combined knockdown of TAp73 and p21 completely abolishes it. Due to the fact that RNPC1 is a target of p73, the mutual regulation between p73 and RNPC1 constitutes a novel feed-forward loop, which might be explored as a target for tumors without a functional p53.

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“…Under unstressed condition, p53 protein is maintained at a low level mostly through ubiquitinationmediated proteosomal degradation (2). In response to DNA damage and other stress signals, p53 is activated and functions as a transcription factor to induce its downstream targets for various cellular processes such as cell cycle arrest [p21, growth arrest and DNA-damage-inducible protein 45 (GADD45)] (3,4), apoptosis [p53 up-regulated modulator of apoptosis protein (PUMA), insulinlike growth factor binding protein 3 (IGFBP3), DR5] (5-7), and senescence [plasminogen activator inhibitor-1 (PAI-1), differentially expressed in chondrocytes protein 1 (DEC1)] (8,9). Although many p53 target genes related to various cellular processes have been identified, these are still insufficient to explain how p53 exerts its functions, in particular cellular senescence.…”

mentioning

confidence: 99%

Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality

Cho

Rossi

Jung

et al. 2013

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

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The tumor suppressor protein p53 plays a crucial role in coordinating cellular processes, such as cell cycle arrest, apoptosis, and senescence. The nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a homophilic adhesion molecule and involved in nerve regeneration. Interestingly, Ninj1 is found to be overexpressed in human cancer, but its role in tumorigenesis is not clear. Here, we found that Ninj1 is transcriptionally regulated by p53 and can be induced by DNA damage in a p53-dependent manner. We also found that knockout or knockdown of Ninj1 increases p53 expression potentially through enhanced p53 mRNA translation. In addition, we found that Ninj1 deficiency suppresses cell proliferation but enhances apoptosis and premature senescence in a p53-dependent manner. Consistent with this, we found that mice heterozygous in ninj1 are hypersensitive to ionizing radiation-induced lethality, along with increased expression of p53 in thymus. Taken together, we provided evidence that Ninj1 is a p53 target and modulates p53 mRNA translation and p53-dependent premature senescence, cell proliferation, apoptosis, and radiationinduced mortality in vitro and in vivo. Thus, we postulate that as a membrane adhesion molecule, Ninj1 is an ideal target to regulate p53 activity via the p53-Ninj1 loop. cellular senescence | radiosensitivity

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DEC1, a Basic Helix-Loop-Helix Transcription Factor and a Novel Target Gene of the p53 Family, Mediates p53-dependent Premature Senescence

Cited by 107 publications

References 46 publications

Differentiated embryo-chondrocyte expressed gene 1 regulates p53-dependent cell survival versus cell death through macrophage inhibitory cytokine-1

Differentiated embryo-chondrocyte expressed gene 1 regulates p53-dependent cell survival versus cell death through macrophage inhibitory cytokine-1

p73 Expression Is Regulated by RNPC1, a Target of the p53 Family, via mRNA Stability

Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality

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