To dissect the role of the globular domains of PGM/versican--a large hyaluronan binding proteoglycan (PG) enriched in tumor lesions--we have stably transduced a human leiomyosarcoma cell line with either the G1 or G3 domain of the PG and subsequently assayed the effect of this manipulation on several cellular processes in vitro and in vivo. G1- and G3-overexpressing cells were found to exhibit an enhanced growth that was more accentuated in the absence of serum components and was seen both when cells were cultured on ECM substrates and in the absence of ECM anchorage. Accordingly, if inoculated subcutaneously into nude mice, G1 transfectants formed larger tumor masses than control cells at the site of implantation, albeit after a certain latency period. Upon binding to cell surface CD44, proliferation of G1-, but not G3-, overexpressing cells were dose dependently inhibited by exogenous hyaluronan (HA) or HA fragments. G1- and G3-transduced cells did not differ in their intrinsic ability to adhere and migrate on various purified ECM components, whereas G1-overproducing sarcoma cells were more invasive than the corresponding G3 mutants, and their locomotion was perturbed by exogenous HA. The augmented anchorage-independent growth exhibited solely by G1-transduced was largely ascribable to a reduced apoptotic rate, thereby indicating a shift in the proliferation--apoptosis equilibrium of the cells toward the former. In fact, G1-overexpressing cells appeared resistant to both cytotoxic drug-induced and Fas-dependent programmed cell death, and this resistance implicated mitochondrial apoptotic genes. The results indicate that the terminal domains of versican may differentially control propagation of tumor cells and diversely modulate their responses to environmental HA.