RB1CC1 Protein Suppresses Type II Collagen Synthesis in Chondrocytes and Causes Dwarfism

Abstract

RB1-inducible coiled-coil 1 (RB1CC1) functions in various processes, such as cell growth, differentiation, senescence, apoptosis, and autophagy. The conditional transgenic mice with cartilage-specific RB1CC1 excess that were used in the present study were made for the first time by the Cre-loxP system. Cartilage-specific RB1CC1 excess caused dwarfism in mice without causing obvious abnormalities in endochondral ossification and subsequent skeletal development from embryo to adult. In vitro and in vivo analysis revealed that the dwarf phenotype in cartilaginous RB1CC1 excess was induced by reductions in the total amount of cartilage and the number of cartilaginous cells, following suppressions of type II collagen synthesis and Erk1/2 signals. In addition, we have demonstrated that two kinds of SNPs (T-547C and C-468T) in the human RB1CC1 promoter have significant influence on the self-transcriptional level. Accordingly, human genotypic variants of RB1CC1 that either stimulate or inhibit RB1CC1 transcription in vivo may cause body size variations.Human diseases associated with COL2A1 (collagen type II ␣1) mutations, such as spondyloepiphyseal dysplasia congenita, achondrogenesis, Czech dysplasia, and hypochondrogenesis, are known. The abnormal pro-␣1(II) chains produced in these diseases cannot be converted into normal type II collagen, the framework to anchor the chondroid matrix, resulting in dwarfism (1-3). SOX9 regulates type II collagen expression (4), and the mutation causes human campomelic dysplasia (5, 6). c-Krox is also known to regulate type II collagen (7), but it is unclear whether the aberrations cause body size abnormalities. Further studies are warranted to investigate mechanisms regulating type II collagen expression and inducing body size abnormalities, such as dwarfism.RB1-inducible coiled-coil 1 (RB1CC1; the symbol referred to here and approved by the Human Genome Organization (HUGO) Gene Nomenclature Committee; also known as FIP200, focal adhesion kinase family-interacting protein of 200 kDa) was identified as a novel molecule that dephosphorylated RB1 (8, 9), and increased RB1 expression (8, 10, 11). RB1CC1 forms a complex with hSNF5 (11), p53 (9, 11), PIASy (a protein inhibitor of activated STAT protein y) (12), and/or the other transcriptional regulators in cell nuclei and enhances the promoter activities of RB1, p16, and p21 (9 -13). A nuclear expression of RB1CC1 is important for tumor suppression through globally transcriptional activation of the RB1 pathway (11), and genetic rearrangement of RB1CC1 is involved in breast cancer tumorigenesis (14, 15). RB1CC1 is located not only in the nucleus but also in the cytoplasm (9,10,16,17), where it plays an essential role in autophagic progression (16 -23), cellular enlargement (24 -26), and apoptosis (27,28). In addition, qualitative or quantitative alterations of RB1CC1 are correlated with various diseases, such as cancer (11, 14, 15, 29 -31), neuronal degeneration (32, 33), inflammatory skin disorder (28), and severe anemia (34).RB1CC1 is pre...

A novel adipokine C1q/TNF-related protein 1 (CTRP1) regulates chondrocyte proliferation and maturation through the ERK1/2 signaling pathway

“…In a variety of chondroprogenitor and chondrocytic cell types, the ERK1/2 pathway acts as an important regulator of cartilage-specific mRNA expression (Bobick and Kulyk, 2008). During chondrocyte maturation, high levels of Col2a1 and aggrecan mRNA require persistently high basal activation of the ERK1/2 pathway (Bobick et al, 2010;Watanabe et al, 2001;Nishimura et al, 2011). Indeed, suppression of the ERK1/2 pathway by a pharmacological inhibitor caused downstream effects including down-regulation of Col2a1 and aggrecan mRNA in maturing N1511 chondrocytes.…”

SNP and INDEL detection in a QTL region on chicken chromosome 2 associated with muscle deposition

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IKKβ in postnatal perichondrium remotely controls endochondral ossification of the growth plate through downregulation of MCP-5

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