Nuclear Retention of the Tumor Suppressor cPML by the Homeodomain Protein TGIF Restricts TGF-β Signaling

Abstract

The homeodomain protein TGIF has been implicated in the negative regulation of TGF-beta signaling. In this study, we report an unexpected role of TGIF in the inhibition of Smad2 phosphorylation, which occurs by a mechanism independent of its association with Smad2. This inhibitory function of TGIF is executed in concert with c-Jun, which facilitates the interaction of TGIF with cPML, resulting in the nuclear sequestration of cPML and the disruption of the cPML-SARA complex. Notably, knockdown of TGIF by siRNA caused increased association of cPML with SARA and cytoplasmic accumulation of cPML. Furthermore, c-Jun(-/-) fibroblasts exhibit enhanced association of cPML with SARA. c-Jun(-/-) fibroblasts also lose their sensitivity to TGIF-mediated disruption of the cPML-SARA complex and of nuclear sequestration of cPML. We suggest that the interaction of TGIF with cPML through c-Jun may negatively regulate TGF-beta signaling through controlling the localization of cPML and, consequently, the assembly of the cPML-SARA complex.

New insights into the role of PML in tumour suppression

“…For instance, upon UV irradiation or cisplatin treatment PML-NDs dramatically reorganise into microspeckles, where the transcription factor c-Jun accumulates [8,82,83]. Unlike ionising radiation, UV damage tends to elicit a response mediated by ATR, which promotes MDM2 sequestration by PML at the nucleolus [78].…”

“…As mentioned above, splice variants of PML localise to the cytoplasm and PML isoform I contains a functional NES [11,58]. Interestingly, cytoplasmic PML isoforms are induced by TGFβ and mediate its growth suppressive functions [59,83] (extensively discussed in [14]). During the cell cycle, the number and shape of PML-NDs are dramatically altered at the S and M phases [105][106][107][108].…”

The Integrin-coupled Signaling Adaptor p130Cas Suppresses Smad3 Function in Transforming Growth Factor-β Signaling

“…For example, it is now known that signaling in the extracellular signal-regulated kinase pathway can lead to direct phosphorylation of spe-cific serine residues in the linker domain of R-Smads, which blocks their nuclear translocation and transcriptional output (Hayashida et al, 2003). The c-Jun NH 2 -terminal kinase pathway also inhibits Smad2-dependent transcription by enhancing complex formation by Smad2 and its corepressor protein TGIF (Seo et al, 2006). In addition, recent reports suggest that integrin signaling also may be involved in negatively regulating TGF-␤ signaling, because adhesion reduces TGF-␤-induced Smad2 phosphorylation and transcriptional activity (Thannickal et al, 2003), and ␤1-integrinmediated adhesion to extracellular matrix (ECM) suppresses TGF-␤-induced apoptosis and growth inhibition .…”

Tgif1 and Tgif2 Repress Expression of the RabGAP Evi5l

“…Tgif1 interacts with general transcriptional corepressors, including CtBP1 and mSin3a, and the related Tgif2 binds mSin3a but lacks the CtBP interaction motif (10)(11)(12). Repression of TGF-␤-dependent gene expression by Tgifs likely involves recruitment of general corepressors to the Smad complex, although other mechanisms for regulating TGF-␤ responses have been proposed (13,14). TGIF1 was first identified by its ability to bind to a specific retinoid response element (RXRE) from the rat CRBPII gene (1).…”