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The Coactivator CRTC1 Promotes Cell Proliferation and Transformation Via AP-1

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The Coactivator CRTC1 Promotes Cell Proliferation and Transformation Via AP-1 The coactivator CRTC1 promotes cell proliferation and transformation via AP-1 Gianluca Canettieria,1, Sonia Conia,2, Michele Della Guardiaa,2, Valentina Nocerinoa, Laura Antonuccia, Laura Di Magnoa, Robert Screatonc, Isabella Screpantia,b, Giuseppe Gianninia, and Alberto Gulinoa,b,d,1 aDepartment of Experimental Medicine and bPasteur Institute, Cenci Bolognetti Foundation, Sapienza University, Rome, Italy; cApoptosis Research Centre, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada; and dNeuromed Institute, Pozzilli, Italy Edited by Peter K. Vogt, Scripps Research Institute, La Jolla, CA, and approved December 5, 2008 (received for review September 3, 2008) Regulation of gene expression in response to mitogenic stimuli is a Besides TPA, AP-1 also is activated by growth factors, cytokines, critical aspect underlying many forms of human cancers. The AP-1 stress signals, and oncoproteins, and thus is involved in various complex mediates the transcriptional response to mitogens, and its cellular processes, including cell proliferation, differentiation, deregulation causes developmental defects and tumors. We report cell survival, apoptosis, and neoplastic transformation (14). that the coactivator CRTC1 cyclic AMP response element-binding Whereas the biological role of the AP-1 transcription factors protein (CREB)-regulated transcription coactivator 1 is a potent and is well established, the molecular mechanism through which indispensable modulator of AP-1 function. After exposure of cells to these factors promote target gene activation remains incom- the AP-1 agonist 12-O-tetradecanoylphorbol-13-acetate (TPA), CRTC1 pletely understood. In this report, we demonstrate that CRTC1 is recruited to AP-1 target gene promoters and associates with c-Jun is a potent, indispensable modulator of AP-1 activity that and c-Fos to activate transcription. CRTC1 consistently synergizes with associates with c-Jun and c-Fos and promotes c-Jun–mediated the proto-oncogene c-Jun to promote cellular growth, whereas AP- cellular proliferation and transformation. 1–dependent proliferation is abrogated in CRTC1-deficient cells. Re- markably, we demonstrate that CRTC1-Maml2 oncoprotein, which Results causes mucoepidermoid carcinomas, binds and activates both c-Jun CRTC1 Is an AP-1 Coactivator and Mediates the Transcriptional Re- and c-Fos. Consequently, ablation of AP-1 function disrupts the sponse to TPA. To evaluate the effect of CRTCs on TPA-induced cellular transformation and proliferation mediated by this oncogene. transcription, we first tested the effect of CRTC1, CRTC2, and Together, these data illustrate a novel mechanism required to couple CRTC3 on the TPA-responsive human matrix metalloproteinase 1 mitogenic signals to the AP-1 gene regulatory program. (MMP1) and 3ϫ AP-1 reporter constructs in HeLa cells. MMP1 contains a TRE (TGACTCA) located at Ϫ72 bp from the tran- AP-1 ͉ CRTC1 ͉ Mect1-Maml2 ͉ Proliferation ͉ Transformation scription start site (16). The 3ϫ AP-1 construct has 3 TRE repeats upstream of the thymidine kinase minimal promoter. As shown in he cyclic AMP response element-binding protein (CREB)- Fig. 1A, CRTC1 had a strong stimulatory effect on both promoters, Tregulated transcription coactivators (CRTCs, originally called whereas CRTC2 and CRTC3 displayed a weaker effect. Thus, we TORCs) are a novel class of signal-dependent CREB coactivators used CRTC1 in all subsequent experiments. identified using a high-throughput expression screen of a mamma- The effect of CRTC1 was synergistic with TPA and was depen- lian cDNA library (1, 2). CRTCs associate with the bZIP region of dent on the AP-1 transcription factor complex, as demonstrated by CREB via their N-terminal region and activate transcription the addition of the AP-1 dominant negative (DN) polypeptide through interactions with components of the basal transcriptional A-Fos (17), which strongly reduced the response to TPA and CRTC1 both alone and in combination (Fig. 1B). The effect also apparatus (1, 3). Under resting conditions, CRTCs are phosphor- ⌬ ylated by sucrose nonfermenting1/AMP-activated protein kinase depended on the TRE; the TRE mutant MMP1 promoter ( TRE) (AMP/SNF) kinases and sequestered in the cytoplasm (4, 5). When construct failed to respond to CRTC1 and TPA (Fig. 1C). the intracellular levels of calcium or cAMP rise, CRTCs are To rule out the involvement of CREB in this process, we dephosphorylated, travel to the nucleus and bind to CREB, thereby performed knockdown experiments using RNA interference. De- activating transcription. Consistent with their role as CREB acti- pletion of CREB using CREB siRNA did not affect CRTC1 vators, CRTCs have been shown to be key regulators of glu- inducibility of the MMP1 gene, whereas knockdown of the AP-1 coneogenesis (5–8), adaptive mitochondrial biogenesis (9), ␤ cell member c-Jun abrogated the transcriptional response to CRTC1 survival (10), and long-term synaptic plasticity (11). (Fig. 1D). In contrast, ablation of CREB, but not c-Jun, disrupted EVX1 Recent observations have suggested that CRTCs also promote the response to CRTC1 of the CREB target promoter (18) (supporting information (SI) Fig. S1), thus demonstrating that activation of other transcription factors besides those of the CREB/ CRTC1 regulation of AP-1 is functionally independent of CREB ATF1 family. Indeed, the phorbol ester 12-O-tetradecanoylphor- and vice versa. bol-13-acetate (TPA) causes CRTC1 nuclear translocation in HeLa To verify that the effect was detectable on endogenous AP-1– cells (12), and deletion of the TPA responsive element (TRE) from responsive genes, we performed RT-PCR on 3 different AP-1 the IL-8 promoter abrogates CRTC1-mediated enhancement (2), suggesting that CRTC1 can stimulate transcriptional output of a TPA-regulated pathway. Recently, it was reported that CRTC1 can Author contributions: G.C., R.S., G.G., and A.G. designed research; G.C., S.C., M.D.G., V.N., be phosphorylated and activated by MEKK1 (13), a critical kinase L.A., and L.D.M. performed research; G.C., S.C., M.D.G., R.S., I.S., and A.G. analyzed data; CELL BIOLOGY activated by several mitogenic stimuli, including TPA. and G.C., R.S., G.G., and A.G. wrote the paper. TPA is a tumor-promoting drug that activates transcription of a The authors declare no conflict of interest. number of genes that typically contain a TPA response element This article is a PNAS Direct Submission. (TRE ϭ TGACTCA) in their promoter regions (14). In turn, the 1To whom correspondence may be addressed. E-mail: [email protected] or TRE is bound by the dimeric AP-1 transcription factor complex, [email protected]. comprising a large family of Fos (c-Fos, FosB, Fra1, Fra-2), Jun 2S.C. and M.D.G. contributed equally to this work. (c-Jun, JunB, JunD), and ATF bZIP proteins (15). The main AP-1 This article contains supporting information online at www.pnas.org/cgi/content/full/ proteins in mammalian cells are c-Jun and c-Fos, with c-Jun the 0808749106/DCSupplemental. most potent transcriptional activator in this group. © 2009 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0808749106 PNAS ͉ February 3, 2009 ͉ vol. 106 ͉ no. 5 ͉ 1445–1450 Downloaded by guest on September 24, 2021 20 A B * C D Con 300 * 6 * 16 800 * 250 CRTC1 WT 200 * 12 600 4 TRE 200 150 8 * 400 * * * **** * 100 Fold Change 2 Fold Change 100 Fold Change Fold change 4 Fold Change 200 * ** *** 50 * * ** ** ** 0 0 0 0 ** 0 SCR CREBi Juni - C1 C2 C3 - C1 C2 C3 C1 -+- + -+-+ C1 - -++ TPA -- + + --++ TPA -+-+ c-Jun A-Fos --- -+++ + CREB pAd-Easy 8 Actin E DMSO TPA FSK+ F G 60 IBMX GFP CRTC1 * * 6 Con TPA 40 H MMP1 4 SCR C1i TPA - + - + * ** MTIIA 20 2 Fold Change * *** Fold change TIMP1 **** ** 0 CRTC1 TIMP1 0 SCR C1i C1 - +-+ -+-+ Actin CRTC1 TPA -- + + --++ GAPDH C1-DN - --- + +++ Actin Fig. 1. CRTC1 promotes the TPA response of AP-1 targets. (A) HeLa cells were transfected with MMP1-luc (Left)or3ϫ AP-1–Luc (Right) plasmids, TK renilla, and plasmids encoding CRTCs (C1, C2, C3: CRTC1–3) for 24 h, and luciferase assays were performed. *P Ͻ .05. (B) HeLa cells were transfected with 3ϫ AP-1–Luc reporter, C1, A-Fos, or empty vector for 24 h and treated with 100 ng/mL of TPA for 10 h, where indicated. *C1, TPA, C1 ϩ TPA versus control, P Ͻ .05; **C1 ϩ A-Fos versus C1, P Ͻ .01; *** TPA ϩ A-Fos versus TPA, P Ͻ .05; ****C1 ϩ TPA ϩ A-Fos versus C1 ϩ TPA, P Ͻ .05. (C) MMP1-Luc (WT) or MMP1 ⌬TRE-Luc reporters (⌬TRE) were transfected in HeLa cells with C1 or empty vector and treated with TPA as before. *C1, TPA, C1 ϩ TPA versus control, P Ͻ .05; **C1, TPA, C1 ϩ TPA ⌬TRE versus C1, TPA, C1 ϩ TPA WT, P Ͻ .01. (D) HeLa cells were transfected with siRNAs for CREB (CREBi), c-Jun (Juni), or nonspecific (SCR), MMP1-Luc, TK renilla, and CRTC1 plasmids for 72 h. The knockdown of c-Jun and CREB was verified by Western blot analysis (Bottom). *SCR CRTC1 versus SCR control, P Ͻ .01; **Juni CRTC1 versus SCR CRTC1, P Ͻ .01. (E) HeLa cells were treated with 100 ng/mL of TPA or 10 ␮M forskolin (FSK) ϩ 40 ␮M IBMX (Left) or infected with the indicated adenoviruses (Right), and RT PCR was performed. (F) HeLa cells were transfected with 3ϫ AP-1–Luc reporter and plasmids expressing C1 or its dominant negative (C1-DN) or empty vector and treated with TPA as above. *C1, TPA, C1 ϩ TPA versus control, P Ͻ .05; **C1 ϩ C1-DN versus C1, P Ͻ .01; ***TPA ϩ C1-DN versus TPA, P Ͻ .01; ****C1 ϩ TPA ϩ C1-DN versus C1 ϩ TPA, P Ͻ .05.
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