Se-Jin Lee

Bio: Se-Jin Lee is an academic researcher from University of Connecticut. The author has contributed to research in topics: Myostatin & Growth differentiation factor. The author has an hindex of 59, co-authored 162 publications receiving 21948 citations. Previous affiliations of Se-Jin Lee include Johns Hopkins University & Johns Hopkins University School of Medicine.

Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.

Abstract: The transforming growth factor-beta (TGF-beta) superfamily encompasses a large group of growth and differentiation factors playing important roles in regulating embryonic development and in maintaining tissue homeostasis in adult animals. Using degenerate polymerase chain reaction, we have identified a new murine TGF-beta family member, growth/differentiation factor-8 (GDF-8), which is expressed specifically in developing and adult skeletal muscle. During early stages of embryogenesis, GDF-8 expression is restricted to the myotome compartment of developing somites. At later stages and in adult animals, GDF-8 is expressed in many different muscles throughout the body. To determine the biological function of GDF-8, we disrupted the GDF-8 gene by gene targeting in mice. GDF-8 null animals are significantly larger than wild-type animals and show a large and widespread increase in skeletal muscle mass. Individual muscles of mutant animals weigh 2-3 times more than those of wild-type animals, and the increase in mass appears to result from a combination of muscle cell hyperplasia and hypertrophy. These results suggest that GDF-8 functions specifically as a negative regulator of skeletal muscle growth.

Double muscling in cattle due to mutations in the myostatin gene

Abstract: Myostatin (GDF-8) is a member of the transforming growth factor beta superfamily of secreted growth and differentiation factors that is essential for proper regulation of skeletal muscle mass in mice. Here we report the myostatin sequences of nine other vertebrate species and the identification of mutations in the coding sequence of bovine myostatin in two breeds of double-muscled cattle, Belgian Blue and Piedmontese, which are known to have an increase in muscle mass relative to conventional cattle. The Belgian Blue myostatin sequence contains an 11-nucleotide deletion in the third exon which causes a frameshift that eliminates virtually all of the mature, active region of the molecule. The Piedmontese myostatin sequence contains a missense mutation in exon 3, resulting in a substitution of tyrosine for an invariant cysteine in the mature region of the protein. The similarity in phenotypes of double-muscled cattle and myostatin null mice suggests that myostatin performs the same biological function in these two species and is a potentially useful target for genetic manipulation in other farm animals.

Regulation of myostatin activity and muscle growth

Abstract: Myostatin is a transforming growth factor-β family member that acts as a negative regulator of skeletal muscle mass. To identify possible myostatin inhibitors that may have applications for promoting muscle growth, we investigated the regulation of myostatin signaling. Myostatin protein purified from mammalian cells consisted of a noncovalently held complex of the N-terminal propeptide and a disulfide-linked dimer of C-terminal fragments. The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA. Binding of myostatin to Act RIIB could be inhibited by the activin-binding protein follistatin and, at higher concentrations, by the myostatin propeptide. To determine the functional significance of these interactions in vivo, we generated transgenic mice expressing high levels of the propeptide, follistatin, or a dominant-negative form of Act RIIB by using a skeletal muscle-specific promoter. Independent transgenic mouse lines for each construct exhibited dramatic increases in muscle mass comparable to those seen in myostatin knockout mice. Our findings suggest that the propeptide, follistatin, or other molecules that block signaling through this pathway may be useful agents for enhancing muscle growth for both human therapeutic and agricultural applications.

Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child

Abstract: Both acquired and inherited disorders of muscle are common; thus, greater understanding of muscle growth and maintenance is important for future therapies. Myostatin down-regulates muscle growth. These investigators describe a mutation in the gene for myostatin in a child with muscle hypertrophy and unusual strength.

Genetic and pharmacological disruption of the TEAD–YAP complex suppresses the oncogenic activity of YAP

Abstract: The Hippo tumor suppressor pathway restricts organ size in Drosophila and mammals by antagonizing the oncoprotein Yki/YAP (Zeng and Hong 2008; Pan 2010; Zhao et al. 2010; Halder and Johnson 2011). Central to the Hippo pathway is a kinase cascade leading from the protein kinase Hpo/Mst to Yki/YAP. The Hippo kinase cascade, in turn, is regulated by a complex network of proteins, which most notably includes the Neurofibromin 2 (NF2)/Merlin tumor suppressor. Consistent with the critical role of Hippo signaling in normal tissue homeostasis, the YAP oncoprotein is overexpressed or hyperactivated in a wide spectrum of human cancers due to YAP locus amplification or genetic/epigenetic inactivation of upstream tumor suppressors. Small molecule inhibitors of YAP will not only provide important tools for pharmacological manipulation of Hippo signaling, but also bear tremendous potential for developing therapeutic drugs against human cancers caused by defective Hippo signaling. As a transcriptional coactivator, YAP has been reported to bind to several DNA-binding transcription factors (for review, see Pan 2010). Among the reported YAP partners, the TEAD/TEF transcription factors are best characterized (Vassilev et al. 2001; Chen et al. 2010; Li et al. 2010). Genetic studies in Drosophila revealed an interesting property of its single TEAD ortholog, Scalloped (Sd): While Sd is required for tissue overgrowth driven by hyperactivated Yki, Sd (but not Yki) is largely dispensable for normal tissue growth (Huang et al. 2005; Wu et al. 2008). Thus, Sd/TEAD may belong to a growing list of genes that contribute to “non-oncogene addiction”—genes that are not mutated in cancers but are critically required for cancer growth (Luo et al. 2009). The dispensability of Sd for normal growth in Drosophila suggests that the mammalian TEAD factors may be ideal targets for selective inhibition of oncogenic growth driven by YAP hyperactivation with minimal effects on normal tissue homeostasis. Although previous studies have shown that the TEAD factors are required for YAP's oncogenic activity in cell cultures (Zhao et al. 2008), whether the TEAD factors (or any of the other reported YAP partners) are required for YAP-mediated tumorigenesis has not been determined in intact mammalian tissues. It also remains to be seen whether inhibition of the mammalian TEAD factors, like loss of Drosophila Sd, has minimal impact on normal tissue homeostasis and physiology. Such information will shed light on the “therapeutic window” of pharmacological strategies aimed at disrupting the TEAD–YAP complex as a selective means against YAP-driven tumorigenesis. Using a combination of genetic suppression in transgenic mice and discovery of lead compounds with in vitro and in vivo activities, we provide here proof of principle that inhibiting TEAD–YAP interactions is a promising and pharmacologically viable strategy against the YAP oncoprotein.

TGF-beta signal transduction.

Abstract: The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.

Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.

Abstract: The transforming growth factor-beta (TGF-beta) superfamily encompasses a large group of growth and differentiation factors playing important roles in regulating embryonic development and in maintaining tissue homeostasis in adult animals. Using degenerate polymerase chain reaction, we have identified a new murine TGF-beta family member, growth/differentiation factor-8 (GDF-8), which is expressed specifically in developing and adult skeletal muscle. During early stages of embryogenesis, GDF-8 expression is restricted to the myotome compartment of developing somites. At later stages and in adult animals, GDF-8 is expressed in many different muscles throughout the body. To determine the biological function of GDF-8, we disrupted the GDF-8 gene by gene targeting in mice. GDF-8 null animals are significantly larger than wild-type animals and show a large and widespread increase in skeletal muscle mass. Individual muscles of mutant animals weigh 2-3 times more than those of wild-type animals, and the increase in mass appears to result from a combination of muscle cell hyperplasia and hypertrophy. These results suggest that GDF-8 functions specifically as a negative regulator of skeletal muscle growth.

Cellular and Molecular Regulation of Muscle Regeneration

Abstract: Charge, Sophie B. P., and Michael A. Rudnicki. Cellular and Molecular Regulation of Muscle Regeneration. Physiol Rev 84: 209–238, 2004; 10.1152/physrev.00019.2003.—Under normal circumstances, mamma...

Adipocyte differentiation from the inside out.

Abstract: Improved knowledge of all aspects of adipose biology will be required to counter the burgeoning epidemic of obesity. Interest in adipogenesis has increased markedly over the past few years with emphasis on the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation. Many different events contribute to the commitment of a mesenchymal stem cell to the adipocyte lineage including the coordination of a complex network of transcription factors, cofactors and signalling intermediates from numerous pathways.