Integration of CREB and bHLH transcriptional signaling pathways through direct heterodimerization of the proteins: role in muscle and testis development.
Integration of CREB and bHLH transcriptional signaling pathways through direct heterodimerization of the proteins: role in muscle and testis development.
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DOI：
10.1002/mrd.20902
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发表时间：
2008-11
影响因子：
2.5
通讯作者：
Skinner MK
中科院分区：
文献类型：
--
作者：
Muir T;Wilson-Rawls J;Stevens JD;Rawls A;Schweitzer R;Kang C;Skinner MK
cAMP应答元件结合蛋白/转录激活因子（CREB/ATF）家族的转录因子是激素应答性的，并且对于几乎所有哺乳动物细胞类型都是关键的。碱性螺旋-环-螺旋（bHLH）转录因子家族在多种细胞类型的发育和分化过程中是重要的。使用酵母双杂交筛选对bHLH蛋白在睾丸支持细胞中的硬化作用和在肌肉发育中的旁轴作用的独立研究提供了新的观察结果，即bHLH蛋白可以直接与ATF/CREB家族成员相互作用。相互作用的分析表明bHLH蛋白的螺旋-环-螺旋结构域直接与CREB 2/ATF 4的亮氨酸拉链（ZIP）区域相互作用以形成异二聚体。使用重组蛋白的免疫共沉淀支持直接bHLH-CREB 2结合相互作用。使用先前的晶体结构对bHLH和ATF 4异二聚体进行结构分析，证明异二聚体可能涉及HLH和Zip结构域，并且具有结合DNA的潜在能力。转染实验表明CREB 2/ATF 4过表达阻断了巩膜轴或旁轴的刺激作用。CREB 1抑制MyoD诱导的C3 H10 T1/2细胞肌原性转化。CREB 2/ATF 4和巩膜轴在胚胎和出生后睾丸发育过程中表达，其中巩膜轴在支持细胞中特异性表达。ATF 4和巩膜轴无效突变小鼠都有类似的成年睾丸生精能力降低的表型。总之，bHLH和CREB家族成员被发现直接异源二聚体化和抑制bHLH二聚体对支持细胞和肌源性前体细胞的作用。观察结果表明，cAMP诱导和bHLH控制的细胞分化之间的直接串扰的机制。
The cAMP response element binding protein/activating transcription factor (CREB/ATF) family of transcription factors is hormone responsive and critical for nearly all mammalian cell types. The basic helix-loop-helix (bHLH) family of transcription factors is important during the development and differentiation of a wide variety of cell types. Independent studies of the role of the bHLH protein scleraxis in testicular Sertoli cells and paraxis in muscle development using yeast-2-hybrid screens provided the novel observation that bHLH proteins can directly interact with ATF/CREB family members. Analysis of the interactions demonstrated the helix-loop-helix domain of bHLH proteins directly interacts with the leucine zipper (ZIP) region of CREB2/ATF4 to form heterodimers. The direct bHLH–CREB2 binding interactions were supported using co-immunoprecipitation of recombinant proteins. Structural analysis of bHLH and ATF4 heterodimer using previous crystal structures demonstrated the heterodimer likely involves the HLH and Zip domains and has the potential capacity to bind DNA. Transfection assays demonstrated CREB2/ATF4 over-expression blocked stimulatory actions of scleraxis or paraxis. CREB1 inhibited MyoD induced myogenic conversion of C3H10T1/2 cells. CREB2/ATF4 and scleraxis are expressed throughout embryonic and postnatal testis development, with scleraxis specifically expressed in Sertoli cells. ATF4 and scleraxis null mutant mice both had similar adult testis phenotypes of reduced spermatogenic capacity. In summary, bHLH and CREB family members were found to directly heterodimerize and inhibit the actions of bHLH dimers on Sertoli cells and myogenic precursor cells. The observations suggest a mechanism for direct cross-talk between cAMP induced and bHLH controlled cellular differentiation.
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影响因子：
11.4
作者：
BRAUN, T;BUSCHHAUSENDENKER, G;ARNOLD, HH
通讯作者：
ARNOLD, HH
影响因子：
4.8
作者：
Dai, YS;Cserjesi, P;Molkentin, JD
通讯作者：
Molkentin, JD
DOI：
10.1073/pnas.88.9.3720
发表时间：
1991-05-01
影响因子：
11.1
作者：
HAI, T;CURRAN, T
通讯作者：
CURRAN, T
影响因子：
64.5
作者：
MA, PCM;ROULD, MA;PABOT, CO
通讯作者：
PABOT, CO
影响因子：
5.3
作者：
LI, L;HELLERHARRISON, R;OLSON, EN
通讯作者：
OLSON, EN