IκB Kinase β (IKKβ) Inhibits p63 Isoform γ (TAp63γ) Transcriptional Activity

Liao, Jingling; Liao, Wenjuan; Zeng, Sheyla X.; Su, Xiaohua; Flores, Elsa R.; Lu, Hua

doi:10.1074/jbc.m113.466540

Cited by 16 publications

(19 citation statements)

References 43 publications

(54 reference statements)

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“…It was previously reported that transcriptional activity of TAp63γ can be down‐regulated via phosphorylation at Ser12 by IκB kinase‐β (IKKβ) [38]. Being consistent with this, we found that S12A mutation, which mimics the dephosphorylation status, increases transcriptional activity of TAp63γ.…”

Section: Discussionsupporting

confidence: 90%

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JNK1 inhibits transcriptional and pro‐apoptotic activity of TAp63γ

Chen

Shi

et al. 2015

FEBS Letters

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a b s t r a c tTAp63c is a homologue of tumor suppressor p53 and functions as a transcriptional factor playing key roles in cell cycle and cell apoptosis. In the present work, we find that JNK1 can physically interact with N-terminal transactivation domain (TAD) of TAp63. Overexpression of JNK1 inhibits TAp63c-mediated transcription, while knockdown or inhibition of endogenous JNK1 increases transactivity of TAp63c. Further study reveals that Ser12 site in TAD is critical for JNK1-mediated inhibition of TAp63c. This JNK1-mediated inhibition can impair pro-apoptotic activity of TAp63c. Together, we report a novel regulation of TAp63c transactivity and pro-apoptotic activity mediated by JNK1.

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Section: Discussionsupporting

confidence: 90%

“…It has been reported that IκB kinase β (IKKβ) phosphorylates Ser12 in TAD of TAp63γ and decreases its transactivity [38]. In this study, we found that JNK1 directly binds to TAD fragment of TAp63γ and inhibits its transcriptional activity.…”

Section: Introductionmentioning

confidence: 63%

JNK1 inhibits transcriptional and pro‐apoptotic activity of TAp63γ

Chen

Shi

et al. 2015

FEBS Letters

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“…The binding of TAp63γ to the putative responsive elements within the CCDC3 enhancer was also confirmed by chromatin immunoprecipitation (ChIP) analysis when HaCat cells, an immortal keratinocyte cell line 15 , with overexpression of flag-TAp63γ were treated with metformin to activate TAp63 transcriptional activity 5 (Fig. 1f ).…”

Section: Resultsmentioning

confidence: 69%

“…Next, we determined if CCDC3 expression is responsive to reagents or signals that affect TAp63 activity. Since our previous study showed that TNFα inhibits TAp63 transcriptional activity 15 , we first tested if TNFα could also inhibit CCDC3 expression. Indeed, this was the case, as treatment of MCF7 cells with TNFα led to the suppression of CCDC3 expression at both the mRNA and protein levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…and genetic and pharmacological interventions that reduce TNFα functions improved obesity and insulin resistance in vitro and vivo 46 – 49 . Previously, we reported that IkappaB kinase beta (IKKbeta) could suppress TAp63 activity by interfering with the interaction between TAp63 and p300 15 . Together, these studies with our present findings suggest a new TNFα-IKK-beta-TAp63-CCDC3 pathway that might offer a novel molecular insight into a better understanding of the HFD-induced hepatic inflammation and steatosis.…”

Section: Discussionmentioning

confidence: 99%

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Ccdc3: A New P63 Target Involved in Regulation Of Liver Lipid Metabolism

Liao

Liu

Zhang

et al. 2017

Sci Rep

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TAp63, a member of the p53 family, has been shown to regulate energy metabolism. Here, we report coiled coil domain-containing 3 (CCDC3) as a new TAp63 target. TAp63, but not ΔNp63, p53 or p73, upregulates CCDC3 expression by directly binding to its enhancer region. The CCDC3 expression is markedly reduced in TAp63-null mouse embryonic fibroblasts and brown adipose tissues and by tumor necrosis factor alpha that reduces p63 transcriptional activity, but induced by metformin, an anti-diabetic drug that activates p63. Also, the expression of CCDC3 is positively correlated with TAp63 levels, but conversely with ΔNp63 levels, during adipocyte differentiation. Interestingly, CCDC3, as a secreted protein, targets liver cancer cells and increases long chain polyunsaturated fatty acids, but decreases ceramide in the cells. CCDC3 alleviates glucose intolerance, insulin resistance and steatosis formation in transgenic CCDC3 mice on high-fat diet (HFD) by reducing the expression of hepatic PPARγ and its target gene CIDEA as well as other genes involved in de novo lipogenesis. Similar results are reproduced by hepatic expression of ectopic CCDC3 in mice on HFD. Altogether, these results demonstrate that CCDC3 modulates liver lipid metabolism by inhibiting liver de novo lipogenesis as a downstream player of the p63 network.

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Pin1 and JNK1 cooperatively modulate TAp63γ

Fan

He²,

et al. 2021

FEBS Open Bio

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The p63 gene encodes at least 10 isoforms, which can be classified into TA and ∆N isotypes (TAp63 and ∆Np63 proteins) according to their differences at the N termini. TAp63γ is an important transcription factor. We previously reported that peptidyl‐prolyl isomerase (PPI) Pin1 directly binds to TAp63γ protein and identified that serine 12 (S12) in the transactivation domain (TAD) of TAp63γ is required for regulation of its transcriptional activity. In the present study, we report that Pin1 stimulates transcriptional and pro‐apoptotic activities of TAp63γ; this Pin1‐mediated stimulation may depend on phosphorylation of S12 mediated by JNK1 and results in striking activation of TAp63γ. JNK1 represses transactivity of TAp63γ in cells without abundant Pin1 proteins and enhances it in the presence of sufficient levels of Pin1. Collectively, our data suggest a novel mechanism for regulation of TAp63γ transactivity: TAp63γ with unphosphorylated S12 is moderately active, phosphorylation at this residue (pS12) makes it hypoactive, and Pin1 binds to the pS12‐P13 motif and makes TAp63γ hyperactive. Our findings will aid in the elucidation of the mechanism underlying modulation of TAp63γ.

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IκB Kinase β (IKKβ) Inhibits p63 Isoform γ (TAp63γ) Transcriptional Activity

Cited by 16 publications

References 43 publications

JNK1 inhibits transcriptional and pro‐apoptotic activity of TAp63γ

JNK1 inhibits transcriptional and pro‐apoptotic activity of TAp63γ

Ccdc3: A New P63 Target Involved in Regulation Of Liver Lipid Metabolism

Pin1 and JNK1 cooperatively modulate TAp63γ

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