| Cartilage is a translucent dense connective tissue functioning in both adult body and embryos where it acts as a model for endochondral ossification. There are essentially three types of cartilages, namely, the hyaline cartilage, the white fibrocartilage, and the yellow or elastic cartilage. Collagen type II is the predominant extracelular matrix (ECM)~1 component in the hyaline cartilage. The collagen type II gene (Col2al) is expressed primarily by proliferating chondrocytes but not by hypertrophic chondrocytes. Mutations in the human Col2al causes skeletal abnormalities characterized by changes in ECM structure and morphology of cartilage and the growth plate, demonstrating the importance of proper expression of Col2a1 for the formation and integrity of these structures. Therefore, elucidating the Regulatory of collagen typell transcription has important implication for understanding cartilage and bone development as well as human disorders.Several transcription factors including SOX9 (Sry-typehigh-mobility-group box) transactivate Col2al expression. SOX9 is a HMG domain transcription factor that is expressed in all cartilage primordia and cartilages during embryonic development In chondrocytes as well as non-chondrocytic cells such as fibroblasts, SOX9 binds to and transactivates the Col2a1 enhancer and a number of other chondrocyte-specific enhancers, supporting that SOX9 may work as a master gene for chondrogenesis. Mutations in the SOX9 gene cause campomelic dysplasia (CD), a severe dwarfism syndrome affecting all cartilage-derived structures. These studies collectively demonstrated an essential role of SOX9 in Col2al expression and cartilage development. In addition to SOX9, two other HMG domain transcription factors, SOX5L and SOX6L, are also implicated in regulation of Col2al expression and chondrogenesis.Alpha A-crystallin-binding protein 1, a ubiquitously expressed zinc finger DNA-binding protein, has two sets of C2-H2 type zinc finger domains located in the amino and carboxyl termini, respectively, and was initially identified by its ability to interact with a functionally important sequence in the mouse alpha A-crystallin gene promoter. Homplogs of the mouse CRYBPl have been identified in Drosophila (Schnurri), C. elegans (SEM-4), rat (AT-BP2), and human (PRDII-BF1/MBP1/HIV-EP1), suggesting a conserved role of CRYBPl through development. The full length CRYBPl gene encodes a 300 kD protein. However, alternatively spliced mRNA also generates truncated molecules including a 200 kD N terminal fragment, and 68 kD, 50 kD, and 90 kD fragments containing the C terminal zincfinger. The function of these molecules are elusive, but Tanaka et al reported that expression of a C terminal fragment (2023-2688) of CRYBP1 in NIH3T3 or a rat chondrosarcoma cell line inhibits Col2al enhancer, which is transactivated by SOX9. Electrophoretic mobility shift assays (EMSA) showed that CRYBP1 binds to a specific sequence within the Col2al enhancer and inhibits the binding of SOX9 to the enhancer. However, the molecular mechanism underlying CRYBP1-mediated repression of Col2a1 has not yet been elucidated.MINT (MSX2-interacting nuclear target protein) is a nuclear matrix protein originally cloned as an interacting protein of MSX2, a homeodomain transcription repressor functioning in the craniofacial skeletal and neural development. MINT belongs to the SPEN(split end) protein family which plays an essential role in multiple developmental events. SPEN proteins vary in a wide range in size (90-600 kD), but are nevertheless characterized by a conserved domain structure, including three repeated RNA recognition motifs (RRMs) near the N terminus and a conserved SPOC (Spen paralog and ortholog C-terminal domain) domain at the C terminus, which mediates interaction with the SMRT/NcoR corepressors. The human homolog of MINT, SHARP, has been identified as a component in transcriptional repression complexes recruited by nuclear receptors. The MINT/SHARP-mediated repression was sensitive to the HDAC inhibitor TSA, and SHARP is a novel component of the HDAC corepressor complex, suggesting that MINT/SHARP represses transcription in an HDAC-dependent fashion. Recently, Kuroda et al... |
