In a BCR/ABL-expressing myeloid precursor cell line, p53 levels were markedly downmodulated. Expression of MDM2, the negative regulator of p53, was upregulated in a tyrosine kinase-dependent manner in growth factor-independent BCR/ABL-expressing cells, and in accelerated phase and blast crisis CML samples. Increased MDM2 expression was associated with enhanced mdm2 mRNA translation, which required the interaction of the La antigen with mdm2 5' UTR. Expression of MDM2 correlated with that of La and was suppressed by La siRNAs and by a dominant negative La mutant, which also enhanced the susceptibility to drug-induced apoptosis of BCR/ABL-transformed cells. By contrast, La overexpression led to increased MDM2 levels and enhanced resistance to apoptosis. Thus, La-dependent activation of mdm2 translation might represent an important molecular mechanism involved in BCR/ABL leukemogenesis.

Decorin, a member of the small leucine-rich proteoglycan gene family, impedes tumor cell growth by down-regulating the epidermal growth factor receptor. Decorin has a complex binding repertoire, thus, we predicted that decorin would modulate the bioactivity of other tyrosine kinase receptors. We discovered that decorin binds directly and with high affinity (Kd = ∼1.5 nM) to Met, the receptor for hepatocyte growth factor (HGF). Binding of decorin to Met is efficiently displaced by HGF and less efficiently by internalin B, a bacterial Met ligand. Interaction of decorin with Met induces transient receptor activation, recruitment of the E3 ubiquitin ligase c-Cbl, and rapid intracellular degradation of Met (half-life = ∼6 min). Decorin suppresses intracellular levels of β-catenin, a known downstream Met effector, and inhibits Met-mediated cell migration and growth. Thus, by antagonistically targeting multiple tyrosine kinase receptors, decorin contributes to reduction in primary tumor growth and metastastic spreading.

Decorin and biglycan are class I small leucine-rich proteoglycans (SLRPs) involved in regulation of collagen fibril and matrix assembly. We hypothesize that tissue-specific matrix assembly, such as in the cornea, requires a coordinate regulation involving multiple SLRPs. To this end, we investigated the expression of decorin and biglycan in the cornea of mice deficient in either SLRP gene and in double-mutant mice. Decorin and biglycan exhibited overlapping spatial expression patterns throughout the corneal stroma with differential temporal expression. Whereas decorin was expressed at relatively high levels in all developmental stages, biglycan expression was high early, decreased during development, and was present at very low levels in the mature cornea. Ultrastructural analyses demonstrated comparable fibril structure in the decorin-and biglycan-null corneas compared with wild-type controls. We found a compensatory up-regulation of biglycan gene expression in the decorindeficient mice, but not the reverse. Notably, the corneas of compound decorin/biglycan-null mice showed severe disruption in fibril structure and organization, especially affecting the posterior corneal regions, corroborating the idea that biglycan compensates for the loss of decorin. Fibrillogenesis assays using recombinant decorin and biglycan confirmed a functional compensation, with both having similar effects at high SLRP/collagen ratios. However, at low ratios decorin was a more efficient regulator. The use of proteoglycan or protein core yielded comparable results. These findings provide firm genetic evidence for an interaction of decorin and biglycan during corneal development and further suggest that decorin has a primary role in regulating fibril assembly, a function that can be fine-tuned by biglycan during early development.The characteristic architecture of different connective tissues is established through tissue-specific regulation of collagen fibrillogenesis and matrix assembly. Multiple steps are involved in collagen fibrillogenesis, including the nucleation of collagen assembly, assembly of immature fibril intermediates, and linear and lateral fibril growth of preformed intermediates (1-5). Each step is independently regulated through interactions of extracellular macromolecules with fibrils. Heterotypic interactions involving different fibril-forming collagens regulate fibril nucleation during development (1, 6). In contrast, interactions involving fibrils and small leucine-rich proteoglycans (SLRPs) 2 are implicated in the regulation of linear and lateral growth of mature fibrils from preformed intermediates (5, 7-10). The focus of this work is to elucidate the differential regulatory role(s) of decorin and biglycan in fibrillogenesis.SLRPs compose a family of five classes of structurally related, but genetically distinct molecules. The members within each class exhibit high protein homology and primary structure identity (11). Decorin and biglycan are class I SLRPs; and fibromodulin, keratocan, and lumican are class II ...

Decorin is not only a regulator of matrix assembly but also a key signaling molecule that modulates the activity of tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR). Decorin evokes protracted internalization of the EGFR via a caveolar-mediated endocytosis, which leads to EGFR degradation and attenuation of its signaling pathway. In this study, we tested if systemic delivery of decorin protein core would affect the biology of an orthotopic squamous carcinoma xenograft. After tumor engraftment, the animals were given intraperitoneal injections of either vehicle or decorin protein core (2.5-10 mg kg ؊1 ) every 2 days for 18 -38 days. This regimen caused a significant and dose-dependent inhibition of the tumor xenograft growth, with a concurrent decrease in mitotic index and a significant increase in apoptosis. Positron emission tomography showed that the metabolic activity of the tumor xenografts was significantly reduced by decorin treatment. Decorin protein core specifically targeted the tumor cells enriched in EGFR and caused a significant downregulation of EGFR and attenuation of its activity. In vitro studies showed that the uptake of decorin by the A431 cells was rapid and caused a protracted down-regulation of the EGFR to levels similar to those observed in the tumor xenografts. Furthermore, decorin induced apoptosis via activation of caspase-3. This could represent an additional mechanism whereby decorin might influence cell growth and survival.The growth of human cancer cells is often dependent or facilitated by the overexpression of receptor tyrosine kinase, such as the EGFR, 2 that provide a growth advantage to the growing and infiltrating neoplasms (1). To prevent the dire consequences of uncontrolled activation of EGFR, a number of negative feedback mechanisms, both extracellular and intracellular, have evolved (2, 3). The prominent role of the EGFR as a crucial relay station among various inputs from the environment and cellular responses has raised the significance of this signaling-transducing receptor to a new level and offers new possibilities for therapeutic intervention (4). We have previously shown that decorin, a secreted small leucine-rich proteoglycan (5, 6), is capable of suppressing the growth of tumor cells with various histogenetic backgrounds (7, 8) by directly interacting with the EGFR (9 -11). Decorin evokes a protracted down-regulation of EGFR tyrosine kinase (12) and other members of the ErbB family of receptor tyrosine kinase (13) and causes an attenuation of the EGFR-mediated mobilization of intracellular calcium (12). Decorin induces expression of the endogenous cyclin-dependent kinase inhibitor p21 WAF1 (14, 15) and a subsequent arrest of the cells in the G 1 phase of the cell cycle (7). These growthsuppressive properties of the soluble decorin and its protein core can also affect murine tumor cells (8) and normal human cells, such as endothelial cells (16) and macrophages (17). A number of observations point toward a key role for decorin in the cont...