Post-transcriptional Control of Cited2 by Transforming Growth Factor β

Chou, Yu‐Ting; Yi, Yang

doi:10.1074/jbc.m601720200

Cited by 36 publications

(28 citation statements)

References 67 publications

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“…It is indicated that TGF-b-mediated CITED2 downregulation in MDA-MB-231 cells occurs post-transcriptionally. 9 Thus, TGF-b mediated downregulation of CITED2 is regulated through a MYCdependent transcriptional control and a MYC independent post-transcriptional mechanism (Supplementary Figure S7).…”

Section: Discussionmentioning

confidence: 99%

CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence

Chou

Hsieh

et al. 2012

Cell Death Differ

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Transforming growth factor-a (TGF-a)-induced proliferation and transforming growth factor-b (TGF-b)-mediated quiescence are intricately balanced in normal lung-tissue homeostasis but are deregulated during neoplastic progression of lung cancer. Here, we show that Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), a novel MYCinteracting transcriptional modulator, responds to TGF-a induction and TGF-b suppression to orchestrate cellular proliferation and quiescence, respectively. Upon TGF-a induction, CITED2 was induced by MYC and further modulated MYC-mediated transcription in a feed-forward manner. CITED2 recruited p300 to promote MYC-p300-mediated transactivation of E2F3, leading to increased G1/S cell cycle progression. Moreover, CITED2 inhibited cellular quiescence by enhancing MYC-mediated suppression of p21 CIP1 . CITED2 interacted with histone deacetylase 1 (HDAC1) and potentiated MYC-HDAC1 complex formation. TGF-b stimulation provoked downregulation of CITED2, which abrogated MYC-HDAC1-mediated p21 CIP1 suppression, causing cellular quiescence. Ectopic CITED2 expression enhanced tumor growth in nude mice; furthermore, CITED2 knockdown caused tumor shrinkage and increased overall host mouse survival rates. Expression of CITED2/MYC/E2F3/ p21 CIP1 signaling molecules was associated with poor prognosis of lung cancer patients. Thus, CITED2 functions as a molecular switch of TGF-a and TGF-b-induced growth control, and MYC-CITED2 signaling axis provides a new index for predicting clinical outcome.

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Section: Discussionmentioning

confidence: 99%

CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence

Chou

Hsieh

et al. 2012

Cell Death Differ

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“…The CITED2 siRNA sequence has been described previously (9, 16). Stable cells were selected in the presence of 1 µg/ml puromycin (Sigma-Aldrich) for one week and utilized for subsequent experiments.…”

Section: Methodsmentioning

confidence: 99%

CITED2 Modulates Breast Cancer Metastatic Ability through Effects on IKKα

Jayaraman

Doucet

Lau

et al. 2016

Molecular Cancer Research

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Previously, we identified the transcriptional co-activator CITED2 as a potential facilitator of bone metastasis using a murine mammary cancer model. Extending these studies to human breast cancer, it was observed that CITED2 mRNA expression was significantly elevated in patient specimens of metastatic breast cancer relative to primary tumors, with highest levels in metastasis to bone relative to non-bone sites. To further evaluate CITED2 functions in breast cancer metastasis, CITED2 expression was stably reduced in the human breast cancer cell lines MDA-MB-231 and MDA-MB-468, which are metastatic in animal models. While CITED2 knockdown had no effect on cell proliferation, cell migration and invasion were significantly reduced, as was the establishment of metastasis following intra-cardiac administration in athymic nude mice. To explore the mechanism behind these effects, gene expression following CITED2 knockdown in MDA-MB-231 cells by cDNA microarray was performed. As confirmed at the mRNA and protein levels in both MDA-MB-231 and MDA-MB-468 cells, expression of the NF-κB regulator IKKα was significantly reduced along with several NF-κB targets with known roles in metastasis (OPN, MMP9, uPA, SPARC, IL-11 and IL-1β). Further, ChIP assay revealed recruitment of CITED2 to the promoter of IKKα, indicating a direct role in regulating its expression. Consistent with reduced IKKα expression, CITED2 knockdown inhibited both canonical and non-canonical NF-κB signaling. Finally, restoration of IKKα expression following CITED2 knockdown in MDA-MB-231 and MDA-MB-468 cells rescued their invasive ability. Collectively, these data demonstrate that CITED2 modulates metastatic ability in human breast cancer cells, at least in part, through the regulation of IKKα. Implications The current study highlights the role of CITED2 in facilitating breast cancer metastasis, partly via regulation of IKKα.

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“…CITED2 is also regulated post-transcriptionally. For instance, CITED2 mRNA instability is mediated via the Smad pathway during TGF-b stimulation (Chou and Yang, 2006). In addition, CITED2 expression can be regulated post-translationally.…”

Section: Hif-1a Inactivation By Cited2 Dh Shin Et Almentioning

confidence: 99%

CITED2 mediates the paradoxical responses of HIF-1α to proteasome inhibition

Shin

Chun

et al. 2007

Oncogene

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Hypoxia-inducible factor-1a (HIF-1a) is destabilized via the ubiquitin-proteasome system. Thus HIF-1a expression is robustly upregulated by proteasome inhibition, but paradoxically its activity is reduced. In the present study, we investigated the mechanism underlying the paradoxical response of HIF-1a to proteasome inhibition. In both Hep3B and HEK293 cells, a proteasome inhibitor MG132 noticeably attenuated hypoxic induction of erythropoietin and VEGF mRNAs. MG132 inactivated HIF-1a C-terminal transactivation domain (CAD), independently of factor inhibiting HIF-1 (FIH) and inhibited p300 recruitment by HIF-1a. We next tested the possibility that CITED2 is involved in the HIF-1 inactivation. CITED2 was found to be degraded via the ubiquitin-proteasome system and thus was stabilized by proteasome inhibition. Both the activity and the p300 binding of HIF-1a were inhibited by CITED2 expression and recovered by CITED2 siRNA in the presence of MG132. These results suggest that CITED2 is stabilized by proteasome inhibition and inactivates HIF-1 by interfering with the HIF-1a-p300 interaction. This may be an important mode-of-action for proteasome inhibition-based cancer therapy.

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Post-transcriptional Control of Cited2 by Transforming Growth Factor β

Cited by 36 publications

References 67 publications

CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence

CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence

CITED2 Modulates Breast Cancer Metastatic Ability through Effects on IKKα

CITED2 mediates the paradoxical responses of HIF-1α to proteasome inhibition

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