The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol-3-OH kinase (PI3K)/Akt pathways are involved in the regulatory mechanisms of several cellular processes including proliferation, differentiation and apoptosis. Here we show that during chick, mouse and zebrafish limb/fin development, a known MAPK/ERK regulator, Mkp3, is induced in the mesenchyme by fibroblast growth factor 8 (FGF8) signalling, through the PI3K/Akt pathway. This correlates with a high level of phosphorylated ERK in the apical ectodermal ridge (AER), where Mkp3 expression is excluded. Conversely, phosphorylated Akt is detected only in the mesenchyme. Constitutively active Mek1, as well as the downregulation of Mkp3 by small interfering RNA (siRNA), induced apoptosis in the mesenchyme. This suggests that MKP3 has a key role in mediating the proliferative, anti-apoptotic signalling of AER-derived FGF8.

Milking the umbilical cord is a safe procedure, reducing the need for RBC transfusions, and the need for circulatory and respiratory support in very preterm infants.

Chondrocytes are critical components for the precise patterning of a developing skeletal framework and articular joint formation. Sox9 is a key transcription factor that is essential for chondrocyte differentiation and chondrocyte-specific gene expressions; however, the precise transcriptional activation mechanism of Sox9 is not fully understood. Here we demonstrate that Sox9 utilizes a cAMP-response element-binding protein (CREB)-binding protein (CBP)/p300 to exert its effects. Sox9 associates with CBP/p300 in the chondrosarcoma cell line SW1353 via its carboxyl termini activation domain in a cell type-specific manner. In promoter assays, CBP/p300 enhances Col2a1, which encodes cartilagespecific type II collagen gene promoter activity via Sox9. Chromatin immunoprecipitation shows that p300 is bound to the Col2a1 promoter region. Furthermore, the CBP/Sox9 complex disrupter peptide suppresses Col2a1 gene expression and chondrogenesis from mesenchymal stem cells. These data demonstrate that CBP and p300 function as co-activators of Sox9 for cartilage tissue-specific gene expression and chondrocyte differentiation.

Complete cytoreduction after peritonectomy and CHPP may improve the survival of patients with peritoneal dissemination from gastric cancer.

Activating transcription factor (ATF) 5 is a transcription factor belonging to the ATF/cAMP-response element-binding protein gene family. We previously reported that ATF5 mRNA expression increased in response to amino acid limitation. The ATF5 gene allows transcription of mRNAs with at least two alternative 5-untranslated regions (5-UTRs), 5-UTR␣ and 5-UTR␤, derived from exon1␣ and exon1␤. 5-UTR␣ contains highly conserved sequences, in which the upstream open reading frames (uORFs) uORF1 and uORF2 are found in many species. This study was designed to investigate the potential role of 5-UTRs in translational control. These 5-UTRs differentially determined translation efficiency from mRNA. The presence of 5-UTR␣ or 5-UTR␤ represses translation from the downstream ATF5 ORF. Moreover, 5-UTR␣-regulated translational repression is released by amino acid limitation or NaAsO 2 exposure. This release was not seen for 5-UTR␤. Mutation of uAUG2 in the uORF2 of 5-UTR␣ restored the basal expression and abolished the positive regulation by amino acid limitation or arsenite exposure. We demonstrated that phosphorylation of eukaryotic initiation factor 2␣ was required for amino acid limitation-induced translational regulation of ATF5. Furthermore, arsenite exposure activated the exogenously expressed hemeregulated inhibitor kinase and induced the phosphorylation of eukaryotic initiation factor 2␣ in nonerythroid cells. These results suggest that translation of ATF5 is regulated by the alternative 5-UTR region of its mRNA, and ATF5 may play a role in protecting cells from amino acid limitation or arsenite-induced oxidative stress.Activating transcription factor (ATF) 2 -5 (formerly designated ATFx) is a transcription factor of the cAMP-response element-binding protein (CREB)/ATF family that was first identified as a protein that binds to the lipopolysaccharide-response element (GPE-1) on the granulocyte colony-stimulating factor (CSF3) gene along with C/EBP␥ (1). It contains a DNAbinding and dimerization domain (bZIP domain) and regulates processes that are involved in cellular differentiation (2, 3), the cell cycle (4), and apoptosis (5, 6). ATF5 represses cAMP-induced transcription in cultured cells (4) and is shown to inhibit apoptosis (6). Angelastro et al. (2) demonstrated that ATF5 inhibits CRE-mediated expression of neural genes and neural differentiation. Cdc34 is the G 2 checkpoint gene, and ATF5 is a target of Cdc34-dependent ubiquitin-mediated proteolysis (4), expression of which is affected by the cell cycle. Recently, Monaco et al. (7) showed that ATF5 is widely expressed in carcinomas, and interference with its function caused apoptotic cell death of neoplastic breast cell lines. This suggests that ATF5 may be a target for cancer therapy and that studies of the mechanism by which ATF5 expression is regulated might be important in the investigation of treatments for cancer.Mammalian cells have the ability to alter their gene expression to adapt to a variety of environmental stresses, including nutrient limitation, ...