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    Screening assay for compounds stimulating somatostatin transcription factor -1 binding to an STF-1 binding site
    1.
    发明授权
    Screening assay for compounds stimulating somatostatin transcription factor -1 binding to an STF-1 binding site 失效
    用于刺激生长抑素转录因子-1与STF-1结合位点结合的化合物的筛选测定

    公开(公告)号：US5849493A

    公开(公告)日：1998-12-15

    申请号：US757316

    申请日：1996-11-27

    申请人： Marc Montminy ,  Bernard Peers

    发明人： Marc Montminy ,  Bernard Peers

    IPC分类号： C12N15/09 ,  A61K48/00 ,  C12Q1/68 ,  G01N33/53 ,  C12Q1/02

    CPC分类号： C12Q1/68 ,  G01N33/53

    摘要： The present invention provides a method to design compounds that mimic the effects of Pbx in stabilizing STF-1 binding. Using well known DNA binding assays, a person having ordinary skill in this art would be able to screen compounds to determine drugs effective in promoting STF-1 binding to DNA. In this way, one will be able to discover new compounds useful in stimulating somatostatin and insulin production.

    摘要翻译： 本发明提供一种设计化合物的方法，其模拟Pbx在稳定STF-1结合中的作用。 使用熟知的DNA结合测定法，本领域普通技术人员将能够筛选化合物以确定有效促进STF-1与DNA结合的药物。 以这种方式，人们将能够发现可用于刺激生长抑素和胰岛素生产的新化合物。

    Protein kinase B/Akt modulators and methods for the use thereof
    4.
    发明授权
    Protein kinase B/Akt modulators and methods for the use thereof 有权
    蛋白激酶B / Akt调节剂及其使用方法

    公开(公告)号：US07220539B1

    公开(公告)日：2007-05-22

    申请号：US10462072

    申请日：2003-06-12

    申请人： Keyong Du ,  Stephan Herzig ,  Marc Montminy

    发明人： Keyong Du ,  Stephan Herzig ,  Marc Montminy

    IPC分类号： C12Q1/00 ,  C12N9/12 ,  C12N1/20 ,  C07K1/00 ,  C07H21/04

    CPC分类号： C12N9/12 ,  C12N9/1205 ,  C12Q1/42 ,  C12Q1/48 ,  G01N2333/4721 ,  G01N2500/02

    摘要： The present invention describes modulator of protein kinase B (PKB)/Akt proteins, exemplified by the Tribbles (TRB) family. An exemplary member of the TRB family, TRB-3, binds to Akt and inhibits its catalytic activity, in turn causing altered regulation of glucose metabolism pathways. TRB-3 expression is strongly induced in the fasting state, and upregulated in mouse models of type II, causing disruptions in insulin signaling. Accordingly, the present invention further provides compositions and methods for disrupting the interaction between such a modulator and PKB/Akt protein kinases. Also provided are methods of determining if a subject has a predisposition to impaired glucose regulation and methods for treating diabetes mellitus using invention compositions.

    摘要翻译： 本发明描述了由Tribbles（TRB）家族举例说明的蛋白激酶B（PKB）/ Akt蛋白的调节剂。 TRB家族的示例性成员TRB-3与Akt结合并抑制其催化活性，反过来导致葡萄糖代谢途径的调节改变。 TRB-3表达在空腹状态下强烈诱导，并且在II型小鼠模型中上调，导致胰岛素信号传导中断。 因此，本发明还提供了用于破坏这种调节剂与PKB / Akt蛋白激酶之间相互作用的组合物和方法。 还提供了确定受试者是否具有受损的葡萄糖调节的倾向的方法以及使用本发明组合物治疗糖尿病的方法。

    Method for screening compounds & uses therefor
    6.
    发明申请
    Method for screening compounds & uses therefor 失效
    化合物及其用途的筛选方法

    公开(公告)号：US20060246418A1

    公开(公告)日：2006-11-02

    申请号：US11398477

    申请日：2006-04-04

    申请人： Marc Montminy

    发明人： Marc Montminy

    IPC分类号： C12Q1/48 ,  C12Q1/00

    CPC分类号： G01N33/5008 ,  C12Q1/485 ,  G01N33/5035 ,  G01N33/5067 ,  G01N33/507 ,  G01N33/6875 ,  G01N2500/00

    摘要： In accordance with the present invention, it has been discovered that glucose and incretin hormones promote pancreatic islet cell survival via the calcium and cAMP dependent induction, respectively, of the transcription factor CREB. Specifically, a signaling module has been identified which mediates cooperative effects of calcium and cAMP on islet cell gene expression by stimulating the dephosphorylation and nuclear entry of TORC2, a cytoplasmic CREB coactivator. The module comprises a cAMP regulated snf1-like kinase called SIK2 and the calcium regulated phosphatase calcineurin, both of which associate with TORC2 in the cytoplasm. TORC2 is repressed under basal conditions through a phosphorylation dependent interaction with 14-3-3 proteins. cAMP and calcium signals stimulate CREB target gene expression via complementary effects on TORC2 dephosphorylation; cAMP disrupts TORC2-associated activity of SIK2 or related family members, whereas calcium induces TORC2 dephosphorylation via calcineurin. These findings provide a novel mechanism by which CREB activates cellular gene expression, depending on nutrient and energy status, and facilitate development of assays to identify compounds which modulate the role of TORCs. In accordance with the present invention, it has been discovered that fasting and energy-sensing pathways regulate the gluconeogenic program in liver by modulating the nuclear entry of a transcriptional coactivator called Transducer of Regulated CREB Activity 2 (TORC2). Hepatic TORC2 over-expression induces fasting hyperglycemia, whereas knockdown of TORC2 leads to fasting hypoglycemia and silencing of the gluconeogenic program. Since a majority of individuals with Type II diabetes exhibit fasting hyperglycemia due to elevated hepatic gluconeogenesis, compounds that enhance TORC2 phosphorylation will find use as therapeutic agents in this setting.

    摘要翻译： 根据本发明，已经发现葡萄糖和肠降血糖素激素分别通过转录因子CREB的钙和cAMP依赖性诱导促进胰岛细胞存活。 具体地，已经鉴定了通过刺激细胞质CREB共激活剂TORC2的去磷酸化和核进入来介导钙和cAMP对胰岛细胞基因表达的协同作用的信号传导模块。 该模块包含称为SIK2的cAMP调节的snf1样激酶和钙调节的磷酸酶钙调神经磷酸酶，两者都与细胞质中的TORC2相关联。 TORC2通过与14-3-3蛋白的磷酸化依赖性相互作用在基础条件下被抑制。 cAMP和钙信号通过对TORC2去磷酸化的互补作用刺激CREB靶基因表达; cAMP破坏SIK2或相关家族成员的TORC2相关活性，而钙通过钙调神经磷酸诱导TORC2去磷酸化。 这些发现提供了CREB激活细胞基因表达的新机制，这取决于营养和能量状态，并促进测定法的发展，以鉴定调节TORC作用的化合物。 根据本发明，已经发现，空腹和能量感应途径通过调节被称为调节性CREB活性2的转导因子（TORC2）的转录共激活因子的核进入调节肝脏中的糖原异常程序。 肝TORC2过表达诱导空腹高血糖，而TORC2的敲低导致空腹低血糖和糖原异常程序的沉默。 由于大多数II型糖尿病患者由于肝脏糖异生升高而呈现禁食性高血糖症，因此在这种情况下可以使用增强TORC2磷酸化作用的化合物作为治疗剂。