Notch-HLH 转录通路
中文名称
通路描述
Notch-HLH 转录通路
NOTCH-HLH 转录通路: Notch 信号通路最初是在果蝇中发现的，并在遗传学、分子生物学、生物化学和细胞水平上进行了详细研究（综述：Justice, 2002; Bray, 2006; Schweisguth, 2004; Louvri, 2006）。在果蝇中，Notch 信号向细胞核传递被认为总是由一种特定的 DNA 结合转录因子 Suppressor of Hairless 介导。在哺乳动物中，同源基因称为 CBF1（或 RBPJkappa），而在线虫中称为 Lag-1，因此将这种保守的转录因子家族称为“CSL”。人类至少有两个 CSL 同源物，现在分别命名为 RBPJ 和 RBPJL。
CSL 是一个双功能 DNA 结合转录因子，在一种情况下介导特定靶基因的抑制，而在另一种情况下激活相同的靶基因。这种双功能是由特定共抑制复合物与共激活复合物在不同上下文中结合介导的，即在没有或存在 Notch 信号的情况下。
在果蝇中，Su(H) 在 Notch 信号缺失时抑制靶基因转录，而在 Notch 信号存在时激活靶基因。至少一些哺乳动物 CSL 同源物也被认为是双功能的，并在 Notch 信号缺失时介导靶基因抑制，在 Notch 信号存在时激活。
Notch 共激活物和共抑制复合物：这种抑制作用至少由一种特定的共抑制复合物（Co-R）介导，该复合物在未激活的 Notch 信号存在时结合到 CSL 上。在果蝇中，这种共抑制复合物至少由三种不同的共抑制蛋白组成：Hairless、Groucho 和 dCtBP（果蝇 C 端结合蛋白）。Hairless 已被证明直接与 Su(H) 结合，Groucho 和 dCtBP 已被证明直接与 Hairless 结合（Barolo, 2002）。所有三种共抑制蛋白在体内 Notch 信号的正常基因调节中都被证明是必要的（Nagel, 2005）。
在哺乳动物中，观察到相同的通路和机制，其中 CSL 蛋白是双功能 DNA 结合转录因子（TFs），结合共抑制复合物以在未激活的 Notch 信号存在时介导抑制，并结合共激活复合物以在激活的 Notch 信号存在时介导激活。然而，在哺乳动物中，可能存在多种共抑制复合物，而不是在果蝇中观察到的单一的 Hairless 共抑制复合物。
在所有系统中的 Notch 信号期间，Notch 跨膜受体被切割，Notch 细胞内区（NICD）转位到细胞核，在那里它作为 CSL 蛋白的特定转录共激活因子发挥作用。在细胞核中，NICD 取代结合到 CSL 上的 Co-R 复合物，从而在细胞核中解除 Notch 靶基因的抑制。一旦结合到 CSL 上，NICD 和 CSL 蛋白招募额外的共激活因子 Mastermind（Mam），形成 CSL-NICD-Mam 三元共激活复合物（Co-A）复合物。该 Co-A 复合物最初被认为足以介导至少一些 Notch 靶基因的激活。然而，现在已有证据表明，至少在某些情况下，仍需要其他共激活因子和额外的 DNA 结合转录因子（综述：Barolo, 2002）。
哺乳动物 CSL 共抑制复合物：在未激活的激活的 Notch 信号存在时，DNA 结合的 CSL 蛋白招募共抑制复合物以维持靶基因处于抑制状态，直到 Notch 被特异性激活。哺乳动物共抑制复合物包括 NCOR 复合物，但也可能包括额外的共抑制蛋白，如 SHARP（综述：Mumm, 2000 和 Kovall, 2007）。CSL NCOR 复合物的确切组成尚不清楚，但在其他通路中，“核心”NCOR 共抑制复合物至少包括一种 NCOR 蛋白（NCOR1、NCOR2、CIR）、一种组蛋白脱乙酰酶蛋白（HDAC1、HDAC2、HDAC3 等）和一种 TBL1 蛋白（TBL1X、TBL1XR1）（综述：Rosenfeld, 2006）。在某些情况下，核心 NCOR 共抑制复合物也可能招募额外的共抑制蛋白或复合物，如 SIN3 复合物，它由 SIN3（SIN3A、SIN3B）和 SAP30 或其他 SIN3 相关蛋白组成，或与其他 SIN3 相关蛋白一起。在某些情况下，CSL 共抑制复合物还包括一种双功能辅因子 SKIP，该辅因子存在于 CSL 共抑制复合物和 CSL 共激活复合物中，并在 Notch 信号激活期间结合 NICD 和共抑制复合物位移（Zhou, 2000）。
哺乳动物 CSL 共激活复合物：Notch 信号激活后，跨膜 Notch 受体的切割释放 Notch 细胞内区（NICD），该区转位到细胞核，在那里它结合到 CSL 并取代 CSL 上的共抑制复合物（综述：Mumm, 2000 和 Kovall, 2007）。由此产生的 CSL-NICD“二元复合物”然后招募额外的共激活因子 Mastermind（Mam），形成三元复合物。三元复合物然后招募额外的、更通用的共激活因子，如 CREB 结合蛋白（CBP）或相关的 p300 共激活因子，以及许多组蛋白乙酰转移酶（HAT）蛋白，包括 GCN5 和 PCAF（Fryer, 2002）。有证据表明 Mam 还可以随后招募特定的激酶，这些激酶磷酸化 NICD，以下调其功能并关闭 Notch 信号（Fryer, 2004）。
转录共激活复合物组合复杂性：HDAC9 至少有 7 种剪接异构体，其中一些具有不同的相互作用和功能特性。异构体 6 和 7 与 NCOR1 相互作用。异构体 1 和 4 与 MEF2（Sparrow, 1999）相互作用，这是 HLH 蛋白的一个特定 DNA 结合辅因子。异构体 3 与 NCOR1 和 MEF2 都相互作用。虽然许多 HDAC 只有一种或两种异构体，但 HDAC9 的这种复杂性说明了这种“通用”转录辅因子可以具有多高的转录复杂度和功能特异性。
NOTCH-HLH 转录通路: Notch 信号通路最初是在果蝇中发现的，并在遗传学、分子生物学、生物化学和细胞水平上进行了详细研究（综述：Justice, 2002; Bray, 2006; Schweisguth, 2004; Louvri, 2006）。在果蝇中，Notch 信号向细胞核传递被认为总是由一种特定的 DNA 结合转录因子 Suppressor of Hairless 介导。在哺乳动物中，同源基因称为 CBF1（或 RBPJkappa），而在线虫中称为 Lag-1，因此将这种保守的转录因子家族称为“CSL”。人类至少有两个 CSL 同源物，现在分别命名为 RBPJ 和 RBPJL。
CSL 是一个双功能 DNA 结合转录因子，在一种情况下介导特定靶基因的抑制，而在另一种情况下激活相同的靶基因。这种双功能是由特定共抑制复合物与共激活复合物在不同上下文中结合介导的，即在没有或存在 Notch 信号的情况下。
在果蝇中，Su(H) 在 Notch 信号缺失时抑制靶基因转录，而在 Notch 信号存在时激活靶基因。至少一些哺乳动物 CSL 同源物也被认为是双功能的，并在 Notch 信号缺失时介导靶基因抑制，在 Notch 信号存在时激活。
Notch 共激活物和共抑制复合物：这种抑制作用至少由一种特定的共抑制复合物（Co-R）介导，该复合物在未激活的 Notch 信号存在时结合到 CSL 上。在果蝇中，这种共抑制复合物至少由三种不同的共抑制蛋白组成：Hairless、Groucho 和 dCtBP（果蝇 C 端结合蛋白）。Hairless 已被证明直接与 Su(H) 结合，Groucho 和 dCtBP 已被证明直接与 Hairless 结合（Barolo, 2002）。所有三种共抑制蛋白在体内 Notch 信号的正常基因调节中都被证明是必要的（Nagel, 2005）。
在哺乳动物中，观察到相同的通路和机制，其中 CSL 蛋白是双功能 DNA 结合转录因子（TFs），结合共抑制复合物以在未激活的 Notch 信号存在时介导抑制，并结合共激活复合物以在激活的 Notch 信号存在时介导激活。然而，在哺乳动物中，可能存在多种共抑制复合物，而不是在果蝇中观察到的单一的 Hairless 共抑制复合物。
在所有系统中的 Notch 信号期间，Notch 跨膜受体被切割，Notch 细胞内区（NICD）转位到细胞核，在那里它作为 CSL 蛋白的特定转录共激活因子发挥作用。在细胞核中，NICD 取代结合到 CSL 上的 Co-R 复合物，从而在细胞核中解除 Notch 靶基因的抑制。一旦结合到 CSL 上，NICD 和 CSL 蛋白招募额外的共激活因子 Mastermind（Mam），形成 CSL-NICD-Mam 三元共激活复合物（Co-A）复合物。该 Co-A 复合物最初被认为足以介导至少一些 Notch 靶基因的激活。然而，现在已有证据表明，至少在某些情况下，仍需要其他共激活因子和额外的 DNA 结合转录因子（综述：Barolo, 2002）。
哺乳动物 CSL 共抑制复合物：在未激活的激活的 Notch 信号存在时，DNA 结合的 CSL 蛋白招募共抑制复合物以维持靶基因处于抑制状态，直到 Notch 被特异性激活。哺乳动物共抑制复合物包括 NCOR 复合物，但也可能包括额外的共抑制蛋白，如 SHARP（综述：Mumm, 2000 和 Kovall, 2007）。CSL NCOR 复合物的确切组成尚不清楚，但在其他通路中，“核心”NCOR 共抑制复合物至少包括一种 NCOR 蛋白（NCOR1、NCOR2、CIR）、一种组蛋白脱乙酰酶蛋白（HDAC1、HDAC2、HDAC3 等）和一种 TBL1 蛋白（TBL1X、TBL1XR1）（综述：Rosenfeld, 2006）。在某些情况下，核心 NCOR 共抑制复合物也可能招募额外的共抑制蛋白或复合物，如 SIN3 复合物，它由 SIN3（SIN3A、SIN3B）和 SAP30 或其他 SIN3 相关蛋白组成，或与其他 SIN3 相关蛋白一起。在某些情况下，CSL 共抑制复合物还包括一种双功能辅因子 SKIP，该辅因子存在于 CSL 共抑制复合物和 CSL 共激活复合物中，并在 Notch 信号激活期间结合 NICD 和共抑制复合物位移（Zhou, 2000）。
哺乳动物 CSL 共激活复合物：Notch 信号激活后，跨膜 Notch 受体的切割释放 Notch 细胞内区（NICD），该区转位到细胞核，在那里它结合到 CSL 并取代 CSL 上的共抑制复合物（综述：Mumm, 2000 和 Kovall, 2007）。由此产生的 CSL-NICD“二元复合物”然后招募额外的共激活因子 Mastermind（Mam），形成三元复合物。三元复合物然后招募额外的、更通用的共激活因子，如 CREB 结合蛋白（CBP）或相关的 p300 共激活因子，以及许多组蛋白乙酰转移酶（HAT）蛋白，包括 GCN5 和 PCAF（Fryer, 2002）。有证据表明 Mam 还可以随后招募特定的激酶，这些激酶磷酸化 NICD，以下调其功能并关闭 Notch 信号（Fryer, 2004）。
转录共激活复合物组合复杂性：HDAC9 至少有 7 种剪接异构体，其中一些具有不同的相互作用和功能特性。异构体 6 和 7 与 NCOR1 相互作用。异构体 1 和 4 与 MEF2（Sparrow, 1999）相互作用，这是 HLH 蛋白的一个特定 DNA 结合辅因子。异构体 3 与 NCOR1 和 MEF2 都相互作用。虽然许多 HDAC 只有一种或两种异构体，但 HDAC9 的这种复杂性说明了这种“通用”转录辅因子可以具有多高的转录复杂度和功能特异性。
英文描述
Notch-HLH transcription pathway THE NOTCH-HLH TRANSCRIPTION PATHWAY:
Notch signaling was first identified in Drosophila, where it has been studied in detail at the genetic, molecular, biochemical and cellular levels (reviewed in Justice, 2002; Bray, 2006; Schweisguth, 2004; Louvri, 2006). In Drosophila, Notch signaling to the nucleus is thought always to be mediated by one specific DNA binding transcription factor, Suppressor of Hairless. In mammals, the homologous genes are called CBF1 (or RBPJkappa), while in worms they are called Lag-1, so that the acronym "CSL" has been given to this conserved transcription factor family. There are at least two human CSL homologues, which are now named RBPJ and RBPJL.
CSL is an example of a bifunctional DNA-binding transcription factor that mediates repression of specific target genes in one context, but activation of the same targets in another context. This bifunctionality is mediated by the association of specific Co-Repressor complexes vs. specific Co-Activator complexes in different contexts, namely in the absence or presence of Notch signaling.
In Drosophila, Su(H) represses target gene transcription in the absence of Notch signaling, but activates target genes during Notch signaling. At least some of the mammalian CSL homologues are believed also to be bifunctional, and to mediate target gene repression in the absence of Notch signaling, and activation in the presence of Notch signaling.
Notch Co-Activator and Co-Repressor complexes: This repression is mediated by at least one specific co-repressor complexes (Co-R) bound to CSL in the absence of Notch signaling. In Drosophila, this co-repressor complex consists of at least three distinct co-repressor proteins: Hairless, Groucho, and dCtBP (Drosophila C-terminal Binding Protein). Hairless has been show to bind directly to Su(H), and Groucho and dCtBP have been shown to bind directly to Hairless (Barolo, 2002). All three of the co-repressor proteins have been shown to be necessary for proper gene regulation during Notch signaling in vivo (Nagel, 2005).
In mammals, the same general pathway and mechanisms are observed, where CSL proteins are bifunctional DNA binding transcription factors (TFs), that bind to Co-Repressor complexes to mediate repression in the absence of Notch signaling, and bind to Co-Activator complexes to mediate activation in the presence of Notch signaling. However, in mammals, there may be multiple co-repressor complexes, rather than the single Hairless co-repressor complex that has been observed in Drosophila.
During Notch signaling in all systems, the Notch transmembrane receptor is cleaved and the Notch intracellular domain (NICD) translocates to the nucleus, where it there functions as a specific transcription co-activator for CSL proteins. In the nucleus, NICD replaces the Co-R complex bound to CSL, thus resulting in de-repression of Notch target genes in the nucleus. Once bound to CSL, NICD and CSL proteins recruit an additional co-activator protein, Mastermind, to form a CSL-NICD-Mam ternary co-activator (Co-A) complex. This Co-A complex was initially thought to be sufficient to mediate activation of at least some Notch target genes. However, there now is evidence that still other co-activators and additional DNA-binding transcription factors are required in at least some contexts (reviewed in Barolo, 2002).
Mammalian CSL Corepressor Complexes: In the absence of activated Notch signaling, DNA-bound CSL proteins recruit a corepressor complex to maintain target genes in the repressed state until Notch is specifically activated. The mammalian corepressor complexes include NCOR complexes, but may also include additional corepressor proteins, such as SHARP (reviewed in Mumm, 2000 and Kovall, 2007). The exact composition of the CSL NCOR complex is not known, but in other pathways the "core" NCOR corepressor complex includes at least one NCOR protein (NCOR1, NCOR2, CIR), one Histone Deacetylase protein (HDAC1, HDAC2, HDAC3, etc), and one TBL1 protein (TBL1X, TBL1XR1) (reviewed in Rosenfeld, 2006). In some contexts, the core NCOR corepressor complex may also recruit additional corepressor proteins or complexes, such as the SIN3 complex, which consists of SIN3 (SIN3A, SIN3B), and SAP30, or other SIN3-associated proteins. An additional CSL - NCOR binding corepressor, SHARP, may also contribute to the CSL corepressor complex in some contexts (Oswald, 2002). The CSL corepressor complex also includes a bifunctional cofactor, SKIP, that is present in both CSL corepressor complexes and CSL coactivator complexes, and may function in the binding of NICD and displacement of the corepressor complex during activated Notch signaling (Zhou, 2000).
Mammalian CSL Coactivator Complexes: Upon activation of Notch signaling, cleavage of the transmembrane Notch receptor releases the Notch Intracellular Domain (NICD), which translocates to the nucleus, where it binds to CSL and displaces the corepressor complex from CSL (reviewed in Mumm, 2000 and Kovall, 2007). The resulting CSL-NICD "binary complex" then recruits an additional coactivator, Mastermind (Mam), to form a ternary complex. The ternary complex then recruits additional, more general coactivators, such as CREB Binding Protein (CBP), or the related p300 coactivator, and a number of Histone Acetytransferase (HAT) proteins, including GCN5 and PCAF (Fryer, 2002). There is evidence that Mam also can subsequently recruit specific kinases that phosphorylate NICD, to downregulate its function and turn off Notch signaling (Fryer, 2004).
Combinatorial Complexity in Transcription Cofactor Complexes: HDAC9 has at least 7 splice isoforms, with some having distinct interaction and functional properties. Isoforms 6 and 7 interact with NCOR1. Isoforms 1 and 4 interact with MEF2 (Sparrow, 1999), which is a specific DNA-binding cofactor for a subset of HLH proteins. Isoform 3 interacts with both NCOR1 and MEF2. Although many HDACs only have one or two isoforms, this complexity for HDAC9 illustrates the level of transcript complexity and functional specificity that such "general" transcriptional cofactors can have.
Notch signaling was first identified in Drosophila, where it has been studied in detail at the genetic, molecular, biochemical and cellular levels (reviewed in Justice, 2002; Bray, 2006; Schweisguth, 2004; Louvri, 2006). In Drosophila, Notch signaling to the nucleus is thought always to be mediated by one specific DNA binding transcription factor, Suppressor of Hairless. In mammals, the homologous genes are called CBF1 (or RBPJkappa), while in worms they are called Lag-1, so that the acronym "CSL" has been given to this conserved transcription factor family. There are at least two human CSL homologues, which are now named RBPJ and RBPJL.
CSL is an example of a bifunctional DNA-binding transcription factor that mediates repression of specific target genes in one context, but activation of the same targets in another context. This bifunctionality is mediated by the association of specific Co-Repressor complexes vs. specific Co-Activator complexes in different contexts, namely in the absence or presence of Notch signaling.
In Drosophila, Su(H) represses target gene transcription in the absence of Notch signaling, but activates target genes during Notch signaling. At least some of the mammalian CSL homologues are believed also to be bifunctional, and to mediate target gene repression in the absence of Notch signaling, and activation in the presence of Notch signaling.
Notch Co-Activator and Co-Repressor complexes: This repression is mediated by at least one specific co-repressor complexes (Co-R) bound to CSL in the absence of Notch signaling. In Drosophila, this co-repressor complex consists of at least three distinct co-repressor proteins: Hairless, Groucho, and dCtBP (Drosophila C-terminal Binding Protein). Hairless has been show to bind directly to Su(H), and Groucho and dCtBP have been shown to bind directly to Hairless (Barolo, 2002). All three of the co-repressor proteins have been shown to be necessary for proper gene regulation during Notch signaling in vivo (Nagel, 2005).
In mammals, the same general pathway and mechanisms are observed, where CSL proteins are bifunctional DNA binding transcription factors (TFs), that bind to Co-Repressor complexes to mediate repression in the absence of Notch signaling, and bind to Co-Activator complexes to mediate activation in the presence of Notch signaling. However, in mammals, there may be multiple co-repressor complexes, rather than the single Hairless co-repressor complex that has been observed in Drosophila.
During Notch signaling in all systems, the Notch transmembrane receptor is cleaved and the Notch intracellular domain (NICD) translocates to the nucleus, where it there functions as a specific transcription co-activator for CSL proteins. In the nucleus, NICD replaces the Co-R complex bound to CSL, thus resulting in de-repression of Notch target genes in the nucleus. Once bound to CSL, NICD and CSL proteins recruit an additional co-activator protein, Mastermind, to form a CSL-NICD-Mam ternary co-activator (Co-A) complex. This Co-A complex was initially thought to be sufficient to mediate activation of at least some Notch target genes. However, there now is evidence that still other co-activators and additional DNA-binding transcription factors are required in at least some contexts (reviewed in Barolo, 2002).
Mammalian CSL Corepressor Complexes: In the absence of activated Notch signaling, DNA-bound CSL proteins recruit a corepressor complex to maintain target genes in the repressed state until Notch is specifically activated. The mammalian corepressor complexes include NCOR complexes, but may also include additional corepressor proteins, such as SHARP (reviewed in Mumm, 2000 and Kovall, 2007). The exact composition of the CSL NCOR complex is not known, but in other pathways the "core" NCOR corepressor complex includes at least one NCOR protein (NCOR1, NCOR2, CIR), one Histone Deacetylase protein (HDAC1, HDAC2, HDAC3, etc), and one TBL1 protein (TBL1X, TBL1XR1) (reviewed in Rosenfeld, 2006). In some contexts, the core NCOR corepressor complex may also recruit additional corepressor proteins or complexes, such as the SIN3 complex, which consists of SIN3 (SIN3A, SIN3B), and SAP30, or other SIN3-associated proteins. An additional CSL - NCOR binding corepressor, SHARP, may also contribute to the CSL corepressor complex in some contexts (Oswald, 2002). The CSL corepressor complex also includes a bifunctional cofactor, SKIP, that is present in both CSL corepressor complexes and CSL coactivator complexes, and may function in the binding of NICD and displacement of the corepressor complex during activated Notch signaling (Zhou, 2000).
Mammalian CSL Coactivator Complexes: Upon activation of Notch signaling, cleavage of the transmembrane Notch receptor releases the Notch Intracellular Domain (NICD), which translocates to the nucleus, where it binds to CSL and displaces the corepressor complex from CSL (reviewed in Mumm, 2000 and Kovall, 2007). The resulting CSL-NICD "binary complex" then recruits an additional coactivator, Mastermind (Mam), to form a ternary complex. The ternary complex then recruits additional, more general coactivators, such as CREB Binding Protein (CBP), or the related p300 coactivator, and a number of Histone Acetytransferase (HAT) proteins, including GCN5 and PCAF (Fryer, 2002). There is evidence that Mam also can subsequently recruit specific kinases that phosphorylate NICD, to downregulate its function and turn off Notch signaling (Fryer, 2004).
Combinatorial Complexity in Transcription Cofactor Complexes: HDAC9 has at least 7 splice isoforms, with some having distinct interaction and functional properties. Isoforms 6 and 7 interact with NCOR1. Isoforms 1 and 4 interact with MEF2 (Sparrow, 1999), which is a specific DNA-binding cofactor for a subset of HLH proteins. Isoform 3 interacts with both NCOR1 and MEF2. Although many HDACs only have one or two isoforms, this complexity for HDAC9 illustrates the level of transcript complexity and functional specificity that such "general" transcriptional cofactors can have.
所含基因
28 个基因