Taken together, the results suggest that, although the binding between SMAD4 and NRF1 moderately strengthened the interaction between SMAD4 and phosphorylated SMAD2/3, NRF1 inhibits TGF-β/SMAD4-induced p15INK4b mRNA expression by interfering with SMAD4 binding to the p15INK4b promoter, thus inhibiting the TGF-β/SMAD4-induced tumor-suppressor function. Here, SMAD2 is linked to neoplasm.