Gliomas are a diverse group of brain tumors of glial origin. Most are characterized by diffuse infiltrative growth in the surrounding brain. In combination with their refractive nature to chemotherapy this makes it almost impossible to cure patients using combinations of conventional therapeutic strategies. The drastically increased knowledge about the molecular underpinnings of gliomas during the last decade has elicited high expectations for a more rational and effective therapy for these tumors. Most studies on the molecular pathways involved in glioma biology thus far had a strong focus on growth factor receptor protein tyrosine kinase (PTK) and phosphatidylinositol phosphatase signaling pathways. Except for the tumor suppressor PTEN, much less attention has been paid to the PTK counterparts, the protein tyrosine phosphatase (PTP) superfamily, in gliomas. PTPs are instrumental in the reversible phosphorylation of tyrosine residues and have emerged as important regulators of signaling pathways that are linked to various developmental and disease-related processes. Here, we provide an overview of the current knowledge on PTP involvement in gliomagenesis. So far, the data point to the potential implication of receptor-type (RPTPδ, DEP1, RPTPμ, RPTPζ) and intracellular (PTP1B, TCPTP, SHP2, PTPN13) classical PTPs, dual-specific PTPs (MKP-1, VHP, PRL-3, KAP, PTEN) and the CDC25B and CDC25C PTPs in glioma biology. Like PTKs, these PTPs may represent promising targets for the development of novel diagnostic and therapeutic strategies in the treatment of high-grade gliomas.
Expression of Oct4 in embryonic stem cells is controlled by a distal upstream stem cell-specific enhancer that is deactivated during retinoic acid (RA)-induced differentiation by an indirect mechanism not involving binding of RA receptors (H. Okazawa, K. Okamoto, F. Ishino, T. Ishino-Kaneko, S. Takeda, Y. Toyoda, M. Muramatsu, and H. Hamada, EMBO J. 10:2997EMBO J. 10: -3005, 1991). Here we report that in RA-treated P19 embryonal carcinoma cells the Oct4 promoter is also subject to negative regulation by RA. The minimal Oct4 promoter sequence mediating repression consists of a promoter-proximal sequence containing a GC-rich SP1 consensus-like sequence and several hormone response element half-sites that can be arranged into direct repeats with different spacing. The GC box binds a nuclear factor that is invariably present in undifferentiated and RA-treated differentiated P19 cells. By contrast, the hormone response element-containing sequence binds factors that are induced following RA treatment. Mutational analysis and competition experiments show that the functional entity binding the RA-induced factor is a direct repeat sequence with a spacing of one nucleotide, previously shown to be a binding site for COUP transcription factors (COUP-TFs). Cotransfected orphan receptors COUP-TF1, ARP-1, and EAR-2 were able to repress the activity of Oct4 promoter-driven reporters in P19 EC cells, albeit with different efficiencies. Furthermore, the negative transcriptional effect of COUP-TFs is dominant over the activating effect of the Oct4 embryonic stem cell-specific enhancer. These results show that negative regulation of Oct4 expression during RA-induced differentiation of embryonic stem cells is controlled by two different mechanisms, including deactivation of the embryonic stem cell-specific enhancer and promoter silencing by orphan nuclear hormone receptors.Among the gene families that play an important role during both vertebrate and invertebrate development is the POU family of transcriptional regulators. Their conserved DNAbinding motif, first recognized among the Pit-1/GHF-1, Octl and Oct2, and Unc83 proteins (27), is involved in binding to the octamer motif (18,95,96), present in the enhancer/ promoter of a variety of eukaryotic genes (77, 85). The Oct family presently consists of a score of members, including Octl (87), Oct2 (56,78), Oct4 (59,68,82), and Oct6 (53,55,88), that, with the exception of Octl, have been implicated in tissue-and stage-specific transcriptional regulation in line with their restricted expression patterns during early embryogenesis and in adult tissues (67,72,79). Expression of Oct4 during early mouse development is restricted to pluripotent stem cells as found in the inner cell mass of blastocyst stage embryos, the pluripotent primitive ectoderm, primordial germ cells, oocytes, and spermatids (68,80,81). In line with its expression in the inner cell mass and primitive neuroectoderm of early mouse embryos, the Oct4 gene is expressed at high levels in both embryonic stem (ES) cells and em...
GH binding to cell surface-localized GH receptors (GHRs) induces a conformational change of the dimerized receptors, resulting in activation of Janus kinase 2 and downstream signaling pathways. Interactions between the extracellular subdomain 2 of adjacent GHR polypeptides result in a 500-A2 contact interface, which has previously been suggested to stabilize the GH-(GHR)2 complex. In this study, we investigated further the role of subdomain 2 in GHR function. Amino acids that participate in (e.g. aspartic acid 152, tyrosine 200, or serine 201) or lie close to (e.g. asparagine 143 or cysteine 241) the contact interface were mutated in rabbit GHR. Surprisingly, none of the mutations affected GHR dimerization, as demonstrated by coimmunoprecipitation of a truncated, epitope-tagged GHR. However, signal transduction of GHR(D152H), GHR(Y200D), and GHR(S201K) mutants was precluded. More insight into the molecular mechanism of the signaling defect was obtained when we examined the effect of the mutations on the integrity of the GH-(GHR)2 complex in a protease-protection assay. In contrast to wild-type GHR, GHR(N143K), and GHR(C241S), the GHR(D152H), GHR(Y200D), and GHR(S201K) mutants were not protected against protease digestion by GH, indicating that a structural change is prevented. Together, we provide new evidence for a critical role of aspartic acid 152, tyrosine 200, and serine 201 of the GHR contact interface in the GH-induced conformational change to a signaling-competent complex rather than in GHR dimerization.
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