Chemistry: molecular biology and microbiology – Spore forming or isolating process
Patent
1994-10-07
1997-10-28
Guzo, David
Chemistry: molecular biology and microbiology
Spore forming or isolating process
4353201, 536 241, 536 243, C07H 2104, C12N 1563, C12N 100, C12N 500
Patent
active
056817355
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the field of gene expression and gene therapy. Specifically, a transcription control element is provided for controlling gene expression in myogenic cells.
BACKGROUND
Vertebrate skeletal muscle fibers are formed by the cellular fusion of progenitor myoblasts, which are embryonic cells that proliferate and populate the muscle-forming regions of embryos. Myogenic lineages become determined during somite morphogenesis, leading to the formation of stably determined myoblasts.
The process of myoblast differentiation into muscle fibers has been investigated in cell cultures of clonal embryonic myoblasts and established myoblast cell lines. In dispersed cell cultures, myoblasts can proliferate clonally in the presence of medium rich in growth factors, but retain their potential to differentiate in fused muscle fibers. Thus, myoblasts are a stably determined cell type, capable of extensive cell division, the progeny of which faithfully inherit their myoblast identity and can express their potential to differentiate into muscle fibers. The growth and differentiation of myoblasts is controlled by extracellular factors, specifically growth factors such as basic fibroblast growth factor (bFGF) and transforming growth factor-.beta. (TGF-.beta.). In the presence of such growth factors, myoblasts proliferate, whereas in reduced concentrations of such factors, myoblasts can exist in the cell cycle in G.sub.1, fuse and differentiate into contractile fibers.
Myogenesis, therefore, involves "determination" of the myoblast lineages in the somite and "differentiation" of myofibers in the muscle-forming regions of the embryo. The molecular mechanisms regulating cell lineage determination have been studied using the mouse cell line C3H1OT1/2 (10T1/2). Konieczny and Emerson, Cell, 38: 791 (1984). This model cell culture system has allowed identification of several mammalian genes (myoD, myogenin, Myf-5 and MRF-4) that regulate the determination of the skeletal lineage. These genes encode transcription factors comprising a subgroup within the basic helix-loop-helix (bHLH) superfamily of Myc-related DNA binding proteins.
It has been determined that the bHLH myogenic regulatory proteins are evolutionarily conserved, as evidenced by amino sequence homology. Pownall et al., Seminars in Devel. Biol., 3: 229-241 (1992); de la Brousse et al., Genes and Devel. 4: 567-581 (1990). Specifically, it has been shown that the protein qmf1, a myoD protein from quail (QMyoD) shares extensive homology with mouse MyoD1, Myf5, myogenin and a MyoD1 sequence from Xenopus Laevis (XMyoD). de la Brousse et al., supra.
As transfected cDNAs, the aforementioned myogenic regulatory factors induce myogenic conversion of multipotential 10T1/2 cells to stably determined populations of proliferative myogenic cells. Consistent with their function in determination, these myogenic regulatory genes are expressed exclusively in skeletal muscle lineages of the embryo, beginning at the early stages of somite formation. Although these transcription factors regulate the determination of skeletal muscle lineage, they themselves are also regulated. The transcriptional regulatory mechanisms that activate their expression in the skeletal muscle lineage of the embryo have heretofore remained unknown.
Because myoblasts are proliferative (i.e., regenerative) and are capable of fusing together to form mature muscle fibers when injected into already-developed muscle tissue, the technique of myoblast transfer has been proposed as a potential therapy or cure for muscular diseases. Myoblast transfer involves injecting myoblast cells into the muscle of a patient requiring treatment. Although developed muscle fibers are not regenerative, the myoblasts are capable of a limited amount of proliferation, thus increasing the number of muscle cells at the location of myoblast infusion. Myoblasts so transferred into mature muscle tissue will proliferate and differentiate into mature muscle fibers. This process involves the fusion of
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Emerson Charles P.
Goldhamer David J.
Fox Chase Cancer Center
Guzo David
Schwartzman Robert
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