A triple carboxylic acid-functionalized RAFT agent platform for the elaboration of well-defined telechelic 3-arm star PDMAc

This communication describes the synthesis of a triple acid-functionalized RAFT agent and its use to prepare well-defined 3-arm star polymers of N,N-dimethylacrylamide (DMAc). A simple esterification reaction allowed the convenient integration of three electron-rich naphthalene recognition units on the RAFT agent platform and subsequently the elaboration of a naphthalene end-decorated telechelic 3-arm star PDMAc. This functionalized star polymer was further exploited to build a hydrogel with a complementary homoditopic host unit featuring tetracationic macrocycle cyclobis(paraquat-p-phenylene) units

Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation

T helper 17 (TH17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor β (TGFβ) is instrumental in TH17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables TH17 cell differentiation remains elusive. Here we reveal that TGFβ enables TH17 cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and TH17 cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of RORγt to enable TH17 cell differentiation. This study reveals a critical mechanism by which TGFβ controls TH17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating TH17-related diseases

Prostate Cancer Induced by Loss of Apc Is Restrained by TGFβ Signaling

Recent work with mouse models of prostate cancer (CaP) has shown that inactivation of TGFβ signaling in prostate epithelium can cooperate with deletion of the Pten tumor suppressor to drive locally aggressive cancer and metastatic disease. Here, we show that inactivating the TGFβ pathway by deleting the gene encoding the TGFβ type II receptor (Tgfbr2) in combination with a deletion of the Apc tumor suppressor gene specifically in mouse prostate epithelium, results in the rapid onset of invasive CaP. Micro-metastases were observed in the lymph nodes and lungs of a proportion of the double mutant mice, whereas no metastases were observed in Apc single mutant mice. Prostate-specific Apc;Tgfbr2 mutants had a lower frequency of metastasis and survived significantly longer than Pten;Tgfbr2 double mutants. However, all Apc;Tgfbr2 mutants developed invasive cancer by 30 weeks of age, whereas invasive cancer was rarely observed in Apc single mutant animals, even by one year of age. Further comparison of the Pten and Apc models of CaP revealed additional differences, including adenosquamous carcinoma in the Apc;Tgfbr2 mutants that was not seen in the Pten model, and a lack of robust induction of the TGFβ pathway in Apc null prostate. In addition to causing high-grade prostate intra-epithelial neoplasia (HGPIN), deletion of either Pten or Apc induced senescence in affected prostate ducts, and this restraint was overcome by loss of Tgfbr2. In summary, this work demonstrates that TGFβ signaling restrains the progression of CaP induced by different tumor suppressor mutations, suggesting that TGFβ signaling exerts a general tumor suppressive effect in prostate.This work was supported by a Program Project Grant from the National Cancer Institute (2P01CA104106 to B. Paschal and D. Wotton), and by a pilot grant from the UVA Cancer Center (funded from the CCSG P30 CA44579, the James and Rebecca CraigFoundation, and UVA Women's Oncology fund) to D. Wotton. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Sharon Birdsall for technical assistance, Anindya Dutta and Dan Gioeli for helpful discussions, and Chun-Song Yang for advice and reagent