The c-Myc protein (Myc) is the most widely expressed member of a small family of highly related cellular oncoproteins that includes L-Myc and N-Myc. Myc is essential for early embryogenesis and regulates cell growth, proliferation, differentiation, and apoptosis. Deregulated Myc expression contributes to tumorigenesis in animal models and is associated with many types of cancer in humans. Most of the biological effects of Myc, including its cellular transformation properties, result from its gene-specific transcription regulatory functions. Myc has a complex N-terminal transcription regulatory domain with both transcription activating and repressive functions and a C-terminal basic helix-loop-helix leucine zipper (bHLHZip) 1 domain, which is required for heterodimerization with its obligatory bHLHZip partner Max and for binding to E-box DNA sequences (consensus CACGTG). The domains of Myc that are essential for cell transformation correspond to domains also required for transcription activation by Myc. These include the bHLHZip domain and two essential amino acid regions within the Myc N-terminal regulatory domain: amino acids 1-110 and 129 -145, which contain, respectively, the two phylogenetically conserved Myc box 1 (MB1) and Myc box 2 (MB2) sequences (reviewed in Refs. 1 and 2). Several different proteins that associate with the N-terminal regulatory domain of Myc have been identified (3). However, generally the precise role(s) of these interactions in Myc functions is still unclear. Of the various Myc-interacting proteins identified so far, the so-called transformation-transactivation domain-associated protein (TRRAP), the human histone acetyltransferase (HAT) GCN5, TIP48, TIP49, and BAF53 proteins appear to play essential roles in Myc-dependent cell transformation (4 -7). These proteins are part of a variety of both shared and distinct multiprotein complexes involved in regulation of chromatin structure via either ATP-dependent nucleosome remodeling (e.g. BAF53-containing SWI/SNF-like complexes) or histone acetylation. In particular, TRRAP is a subunit of the TIP48/TIP49-containing TIP60 HAT complex, which preferentially acetylates histone H4 (and H2A) within nucleosomes (8), a related p400 complex that appears to lack TIP60 and HAT activity (9), a novel TRRAP-BAF53 HAT complex that acetylates preferentially nucleosomal histones H4 and H2A (7), and at least three distinct human complexes related to the yeast SAGA coactivator complex that preferentially acetylate nucleosomal histone H3: the PCAF (p300/CBPassociated factor) complex (10), and the two distinct human GCN5-containing complexes STAGA (11) and TFTC (12). Some of these TRRAP-containing complexes have been implicated in transcription regulation and/or DNA repair within chromatin, although the detailed mechanisms are still unclear. Thus, the essential role of TRRAP in transformation by Myc may result from its possible function as an adaptor linking Myc to one or several of the above HAT complexes and cognate activities. Indeed, TRRAP has been shown t...
The I1-imidazoline receptor is a novel drug target for hypertension and insulin resistance which are major disorders associated with Type II diabetes. In the present study, we examined the effects of a novel imidazoline agonist S43126 on calcium fluxes and insulin secretion from Min6 β-cells. We also examined the effects of S43126 on the induction of IRAS, and phosphorylation of components in the I1-imidazoline signaling pathways, namely ERK and PKB. Min6 β-cells were treated with varying doses of S43126 [10−8M to 10−5M] for various time (5–60mins). S43126 at higher dose [10−5M] stimulated insulin secretion under elevated glucose concentration compared to basal. In addition, insulin secretion and Ca2+ influx mediated by S43126 [10−5M] were decreased following co-treatment with efaroxan (I1-antagonist) and nifedipine (L-type voltage-gated Ca2+-channel blocker) at various times (5–60mins). Furthermore, S43126 at [10−5M] increased Ca2+ oscillation, [Ca2+] and 45Ca2+ uptake in a time and dose-dependent manner. Moreover, Western blot analysis of treated samples showed that S43126 caused an increased protein expression of IRAS as well as phosphorylation of both ERK1/2 and PKB in a concentration-dependent manner. We conclude that S43126 exerts its insulinotropic effect in a glucose dependent manner by a mechanism involving L-type calcium channels and imidazoline I1-receptors.
Abstract:The I 1 -imidazoline receptor is a novel target for drug development for hypertension and insulin resistance, major disorders associated with type 2 diabetes. In the present study, we examined the effects of a novel imidazoline agonist S43126, on phosphorylation of protein kinase B (PKB/Akt) and extracellular signal-regulated kinase (ERK1/2) in PC12 cells. We further examined the effects of S43126 on insulin stimulated PKB and ERK phosphorylation. PC12 cells were treated with varying doses of S43126 (10 -10 to 10 -6 M) or insulin (10 -10 to 10 -6 M) or combination treatment with insulin (10 -6 M) and varying doses of S43126 (10 -6 -10 -11 M) for 10 min. Western blot analysis of treated samples showed that S43126 increased both ERK1/2 and PKB phosphorylation by 5 fold. Combination treatment with insulin (10 -6 M) and varying doses of S43126 (10 -6 -10 -11 M) enhanced phosphorylation of PKB and ERK1/2 above the level of insulin alone, in a dose and time dependent manner. Treatment with siRNA against Nischarin (mouse homologue of I 1 -imidazoline receptor) reduced the phosphorylation of both ERK and PKB following combination treatments. These results indicate that S43126 has the potential to augment insulin action and should be further studied as a possible candidate drug for the treatment of insulin resistance states.
The I1‐imidazoline receptor is a novel drug target for hypertension and insulin resistance associated with Type II diabetes. We hypothesize that the novel I1‐imidazoline agonist S43126, act centrally to lower blood pressure and enhance glucose uptake by causing insulin release and phosphorylation of protein kinase B (PKB). Blood pressure measurements were made following cumulative injection of S43126 (5 nmol) and moxonidine (5nmol) into the brain of SHR. ELISA was used to measure insulin release from Min 6 cells under conditions of high (16.8mM), or low (2.8mM) glucose, following treatment with varying doses of S43126 [10‐8M to 10‐5M], for various times (5–60mins), in the presence or absence of inhibitors. Our results showed that both S43126 and moxonidine lowered arterial pressure by 20 mmHg and 45 mmHg respectively. S43126 [10‐5M] stimulated insulin secretion under elevated glucose concentration compared to basal. In addition, insulin secretion and Ca2+ influx mediated by S43126 [10‐5M] were decreased by efaroxan and nifedipine. Furthermore, S43126 [10‐5M] increased [Ca2+]i and 45Ca2+ uptake in a time and dose‐dependent manner. S43126 also caused increased protein expression of Imidazoline Receptor Antisera‐Selected (IRAS) protein, as well as increased phosphorylation of both ERK1/2 and PKB, in a dose‐dependent manner. These data indicate that S43126 may be useful in treating metabolic diseases.
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