[Abstract unavailable

The stress-activated protein kinases (SAPKs), which are identical to the c-Jun amino-terminal kinases (JNKs), are activated in response to a variety of cellular stresses, including DNA damage, heat shock or tumour-necrosis factor-alpha. SAPK, a subfamily of the mitogen-activated protein (MAP) kinases, is a major protein kinase that phosphorylates c-Jun and other transcription factors. SAPK phosphorylation of transcription factors is important in stress-activated signalling cascades. Here we report that the protein p21 WAF1/CIP1/Sd:1, a DNA-damage-inducible cell-cycle inhibitor, acts as an inhibitor of the SAPK group of mammalian MAP kinases. This highlights a new biochemical activity of p21, which may provide the first evidence for a non-enzymatic inhibitory protein for SAPK. We suggest that p21, by inhibiting SAPK, may participate in regulating signalling cascades that are activated by cellular stresses such as DNA damage.

Gliomas are associated with high mortality because of their exceedingly invasive character. As these tumors acquire their invasiveness from low-grade tumors, it is very important to understand the detailed molecular mechanisms of invasion onset. Recent evidences suggest the significant role of microRNAs in tumor invasion. Thus, we hypothesized that deregulation of microRNAs may be important for the malignant progression of gliomas. We found that the aberrant expression of miR-21 is responsible for glioma invasion by disrupting the negative feedback circuit of Ras/MAPK signaling, which is mediated by Spry2. Upregulation of miR-21 was triggered by tumor microenvironmental factors such as hyaluronan and growth factors in glioma cells lacking functional phosphatase and tensin homolog (PTEN), but not harboring wild-type PTEN. Consistently with these in vitro results, Spry2 protein levels were significantly decreased in 79.7% of invasive WHO grade II-IV human glioma tissues, but not in non-invasive grade I and normal tissues. The Spry2 protein levels were not correlated with their mRNA levels, but inversely correlated with miR-21 levels. Taken together, these results suggest that the posttranscriptional regulation of Spry2 by miR-21 has an essential role on the malignant progression of human gliomas. Thus, Spry2 may be a novel therapeutic target for treating gliomas.

The distribution of type I calmodulin-sensitive adenylyl cyclase in bovine and rat tissues was examined by northern blot analysis and in situ hybridization. Northern blot analysis using poly(A)(+)-selected RNA from various bovine tissues indicated that mRNA for type I adenylyl cyclase was found only in brain, retina, and adrenal medulla, suggesting that this enzyme is neural specific. In situ hybridization studies using bovine, rabbit, and rat retina indicated that mRNA for type I adenylyl cyclase is found in all three nuclear layers of the neural retina and is particularly abundant in the inner segment of the photoreceptor cells. The neural-specific distribution of type I adenylyl cyclase mRNA and its restricted expression in areas of brain implicated in neuroplasticity are consistent with the proposal that this enzyme plays an important role in various neuronal functions including learning and memory.

Calcium and integrin binding protein 1 (CIB1) is a Ca 2+ -binding protein of 22 kDa that was initially identified as a protein that interacts with integrin α IIb . Although it interacts with various proteins and has been implicated in diverse cellular functions, the molecular mechanism by which CIB1 regulates intracellular signaling networks has remained unclear. We now show that, by targeting apoptosis signal-regulating kinase 1 (ASK1), CIB1 negatively regulates stress-activated MAPK signaling pathways. CIB1 was thus shown to bind to ASK1, to interfere with the recruitment of TRAF2 to ASK1, and to inhibit the autophosphorylation of ASK1 on threonine-838, thereby blocking ASK1 activation. Furthermore, CIB1 mitigated apoptotic cell death initiated either by TNF-α in breast cancer MCF7 cells or by 6-hydroxydopamine (6-OHDA) in dopaminergic cells. Ca 2+ influx induced by membrane depolarization reversed the inhibitory effect of CIB1 on 6-OHDA-induced ASK1 activation and cell death in dopaminergic neurons. These observations thus suggest that CIB1 functions as a Ca 2+ -sensitive negative regulator of ASK1-mediated signaling events.