Characterization of the FHL protein family

骨骼肌对运动或机械负荷作出反应，这一过程被称为肥厚。肥大是由一群未成熟的肌肉细胞（称为成肌细胞）开始的，这些细胞融合形成肌管，然后成熟形成肌纤维（分化）。许多参与激活和或失活级联的蛋白质对调节肥厚（肥厚信号）很重要。骨骼肌不能诱导肥大可导致肌肉变性。FHL蛋白在骨骼肌中高度表达。FHL蛋白是指导蛋白质复合物组装形成肌肉收缩机制（肌节）的分子支架。我们认为FHL蛋白将启动调节骨骼肌肥大。FHL1水平升高与骨骼肌肥大相关。然而，尚不清楚FHL1的增加是否足以直接诱导肥厚。我们用基因工程小鼠在骨骼肌中特异性表达高水平的FHL1 （FHL1转基因小鼠），这些小鼠表现出肌肉增大。FHL1转基因小鼠的肌肉纤维更大，比非转基因小鼠强壮7倍。我们目前正在研究哪些细胞信号通路受到FHL1升高的影响。我们也在研究另一个家族成员FHL3在未成熟成肌细胞分化中的作用，这是胚胎和出生后骨骼肌（肥大）发育所必需的过程。在细胞核中，FHL2调节控制细胞生长和死亡的基因，在前列腺癌活检中检测到核中FHL2水平升高。最近，我们证明了FHL2通过一种叫做丝蛋白的蛋白质与细胞核结合并被隔离。我们正在研究人类黑色素瘤细胞中由于基因突变而缺乏丝蛋白的FHL2介导的基因调控，并将确定这如何影响FHL2在肌肉中的功能。

Skeletal muscle responds to exercise or mechanical load, in a process known as hypertrophy. Hypertrophy is initiated by a population of immature muscle cells known as myoblasts which fuse to form myotubes, and then mature to form muscle fibers (differentiation). Many proteins involved in a cascade of activation and-or deactivation are important for regulating hypertrophy (hypertrophic signaling). Failure of skeletal muscle to induce hypertrophy can lead to muscle degeneration. The FHL proteins are highly expressed in skeletal muscle. FHL proteins are molecular scaffolds which direct assembly of protein complexes to form the muscle contraction machinery (sarcomere). We propose FHL proteins will initiate-regulate skeletal muscle hypertrophy. Increased levels of FHL1 correlate with skeletal muscle hypertrophy. However, it is unclear if increased FHL1 is alone sufficient to induce hypertrophy directly. We have genetically engineered mice to express elevated levels of FHL1 specifically in skeletal muscles (FHL1 transgenic mice) and these mice show muscle enlargement. FHL1 transgenic mice have larger muscle fibers and are >7-fold stronger than non-transgenic littermates. We are currently examining which cell signaling pathways are affected by elevated FHL1. We are also investigating the role of another family member FHL3 in the differentiation of immature myoblasts, a process essential for both embryonic and postnatal skeletal muscle (hypertrophy) development. In the cell nucleus, FHL2 regulates genes which control cell growth and death and increased nuclear levels of FHL2 been detected in prostate cancer biopsies. Recently we demonstrated that FHL2 binds and is sequestered from the nucleus, by a protein, filamin. We are investigating the FHL2-mediated regulation of genes in human melanoma cells, which due to gene mutation are devoid of filamin and will determine how this affects FHL2 function in muscle.