Gluderer Silvia, Brunner Erich, Germann Markus, Jovaisaite Virginija, Li Changqing, Rentsch Cyrill A, Hafen Ernst, Stocker Hugo
Institute of Molecular Systems Biology, ETH Zurich, Wolfgang-Pauli-Strasse 16, 8093 Zurich, Switzerland.
J Biol. 2010;9(1):9. doi: 10.1186/jbiol216. Epub 2010 Feb 11.
The TSC-22 domain family (TSC22DF) consists of putative transcription factors harboring a DNA-binding TSC-box and an adjacent leucine zipper at their carboxyl termini. Both short and long TSC22DF isoforms are conserved from flies to humans. Whereas the short isoforms include the tumor suppressor TSC-22 (Transforming growth factor-beta1 stimulated clone-22), the long isoforms are largely uncharacterized. In Drosophila, the long isoform Bunched A (BunA) acts as a growth promoter, but how BunA controls growth has remained obscure.
In order to test for functional conservation among TSC22DF members, we expressed the human TSC22DF proteins in the fly and found that all long isoforms can replace BunA function. Furthermore, we combined a proteomics-based approach with a genetic screen to identify proteins that interact with BunA. Madm (Mlf1 adapter molecule) physically associates with BunA via a conserved motif that is only contained in long TSC22DF proteins. Moreover, Drosophila Madm acts as a growth-promoting gene that displays growth phenotypes strikingly similar to bunA phenotypes. When overexpressed, Madm and BunA synergize to increase organ growth.
The growth-promoting potential of long TSC22DF proteins is evolutionarily conserved. Furthermore, we provide biochemical and genetic evidence for a growth-regulating complex involving the long TSC22DF protein BunA and the adapter molecule Madm.
TSC-22结构域家族（TSC22DF）由假定的转录因子组成，这些转录因子在其羧基末端含有一个DNA结合TSC框和一个相邻的亮氨酸拉链。TSC22DF的短异构体和长异构体从果蝇到人类都是保守的。短异构体包括肿瘤抑制因子TSC-22（转化生长因子-β1刺激克隆-22），而长异构体在很大程度上尚未得到充分研究。在果蝇中，长异构体束状A（BunA）作为一种生长促进因子，但BunA如何控制生长仍不清楚。
为了测试TSC22DF成员之间的功能保守性，我们在果蝇中表达了人类TSC22DF蛋白，发现所有长异构体都可以替代BunA的功能。此外，我们将基于蛋白质组学的方法与遗传筛选相结合，以鉴定与BunA相互作用的蛋白质。Madm（Mlf1衔接分子）通过一个仅存在于TSC22DF长蛋白中的保守基序与BunA发生物理关联。此外，果蝇Madm作为一个生长促进基因，表现出与bunA表型惊人相似的生长表型。当过度表达时，Madm和BunA协同作用以增加器官生长。
TSC22DF长蛋白的生长促进潜力在进化上是保守的。此外，我们提供了生化和遗传证据，证明存在一个涉及TSC22DF长蛋白BunA和衔接分子Madm的生长调节复合物。
