Activation of the cyclin D1 gene by the E1A-associated protein p300 through AP-1 inhibits cellular apoptosis

The adenovirus E1A protein interferes with regulators of apoptosis and growth by physically interacting with cell cycle regulatory proteins including the retinoblastoma tumor suppressor protein and the coactivator proteins p300/CBP (where CBP is the CREB-binding protein). The p300/CBP proteins occupy a pivotal role in regulating mitogenic signaling and apoptosis. The mechanisms by which cell cycle control genes are directly regulated by p300 remain to be determined. The cyclin D1 gene, which is overexpressed in many different tumor types, encodes a regulatory subunit of a holoenzyme that phosphorylates and inactivates PRB. In the present study E1A12S inhibited the cyclin D1 promoter via the amino-terminal p300/CBP binding domain in human choriocarcinoma JEG-3 cells. p300 induced cyclin D1 protein abundance, and p300, but not CBP, induced the cyclin D1 promoter. cyclin D1 or p300 overexpression inhibited apoptosis in JEG-3 cells. The CH3 region of p300, which was required for induction of cyclin D1, was also required for the inhibition of apoptosis. p300 activated the cyclin D1 promoter through an activator protein-1 (AP-1) site at -954 and was identified within a DNA-bound complex with c-Jun at the AP-1 site. Apoptosis rates of embryonic fibroblasts derived from mice homozygously deleted of the cyclin D1 gene (cyclin D1−/−) were increased compared with wild type control on several distinct matrices. p300 inhibited apoptosis in cyclin D1+/+ fibroblasts but increased apoptosis in cyclin D1 −/− cells. The anti-apoptotic function of cyclin D1, demonstrated by sub-G1 analysis and annexin V staining, may contribute to its cellular transforming and cooperative oncogenic properties

Nerve Growth Factor Regulation of Cyclin D1 in PC12 Cells through a p21RAS Extracellular Signal-regulated Kinase Pathway Requires Cooperative Interactions between Sp1 and Nuclear Factor-κB

The PC12 pheochromocytoma cell line responds to nerve growth factor (NGF) by exiting from the cell cycle and differentiating to induce extending neurites. Cyclin D1 is an important regulator of G1/S phase cell cycle progression, and it is known to play a role in myocyte differentiation in cultured cells. Herein, NGF induced cyclin D1 promoter, mRNA, and protein expression via the p21RAS pathway. Antisense- or small interfering RNA to cyclin D1 abolished NGF-mediated neurite outgrowth, demonstrating the essential role of cyclin D1 in NGF-mediated differentiation. Expression vectors encoding mutants of the Ras/mitogen-activated protein kinase pathway, and chemical inhibitors, demonstrated NGF induction of cyclin D1 involved cooperative interactions of extracellular signal-regulated kinase, p38, and phosphatidylinositol 3-kinase pathways downstream of p21RAS. NGF induced the cyclin D1 promoter via Sp1, nuclear factor-κB, and cAMP-response element/activated transcription factor sites. NGF induction via Sp1 involved the formation of a Sp1/p50/p107 complex. Cyclin D1 induction by NGF governs differentiation and neurite outgrowth in PC12 cells

Transcatheter aortic valve implantation versus conservative management for severe aortic stenosis in real clinical practice

竹治, 泰明谷口, 智彦森本, 剛齋藤, 成達安藤, 献児白井, 伸一新井, 善雄坂口, 元一福, 康志川瀬, 裕一小宮, 達彦江原, 夏彦北井, 豪小山, 忠明渡邉, 真渡部, 宏俊塩見, 紘樹南野-牟田, 恵里松田, 真太郎夜久, 英憲芳川, 裕亮山﨑, 和裕川東, 正英坂本, 和久田村, 俊寛三宅, 誠阪口, 仁寿村田, 耕一郎中井, 真尚泉, 知里稲田, 司竹内, 泰代山根, 啓一郎田村, 崇豊福, 守石井, 充猪子, 森明池田, 智之石井, 克尚堀田, 幸造陣内, 俊和東谷, 暢也犬塚, 康孝湊谷, 謙司木村, 剛Background: Transcatheter aortic valve implantation (TAVI) is criticized by some as an expensive treatment in super-elder patients with limited life expectancy. However, there is a knowledge gap regarding the magnitude of clinical benefit provided by TAVI in comparison with conservative management in patients with severe aortic stenosis (AS) in real clinical practice, which would be important in the decision making for TAVI. Methods: We combined two independent registries, namely CURRENT AS and K-TAVI registries. CURRENT AS was a multicenter registry enrolling 3815 consecutive patients with severe AS irrespective to treatment modalities between January 2003 and December 2011. K-TAVI was a multicenter, prospective registry including 449 consecutive patients with severe AS, who underwent TAVI with SAPIEN XT balloon-expandable valves between October 2013 and June 2016. In these 2 registries, 449 patients received TAVI and 894 patients were managed with conservative strategy. We conducted propensity score matching and finally obtained a cohort of 556 patients (278 patients for each group) for the analysis. The primary outcome measures were all-cause death and heart failure (HF) hospitalization at 2-year. Results: The cumulative 2-year incidences of all-cause death and HF hospitalization were significantly lower in the TAVI group than in the conservative group (16.8% versus 36.6%, P<0.001, and 10.7% versus 37.2%, P<0.001). After adjusting the residual confounders, TAVI reduced the risks of all-cause death (HR, 0.46; 95%CI, 0.32–0.69; P = 0.0001) and HF hospitalizations (HR, 0.25; 95%CI, 0.16–0.40; P<0.0001) compared with conservative strategy. There was no difference in the cumulative incidence of non-cardiovascular death between the 2 groups. Conclusions: TAVI in the early Japanese experience was associated with striking risk reduction for all-cause death as well as HF hospitalization as compared with the historical cohort of patients with severe AS who were managed conservatively just before introduction of TAVI in Japan