We have demonstrated previously that the Myc
oncoprotein blocks
cancer cell differentiation by forming a novel transcriptional repressor complex with
histone deacetylase and inhibiting gene transcription of
tissue transglutaminase (TG2). Moreover, induction of TG2 gene transcription and transamidase activity is essential for the differentiating effects of
retinoids in
cancer cells. Here, we show that two structurally distinct TG2
protein isoforms, the full-length (TG2-L) and the short form (TG2-S), exert opposing effects on cell differentiation. Repression of TG2-L with
small interfering RNA, which did not affect TG2-S expression, induced dramatic neuritic differentiation in
neuroblastoma cells. In contrast, overexpression of TG2-S or a
GTP-binding-deficient mutant of TG2-L (R580A), both of which lack the
GTP-binding Arg-580 residue, induced
neuroblastoma cell differentiation, which was blocked by an inhibitor of transamidase activity. Whereas N-Myc repressed and
retinoid activated both TG2
isoforms, repression of TG2-L, but not simultaneous repression of TG2-L and TG2-S, enhanced
neuroblastoma cell differentiation due to N-Myc
small interfering RNA or
retinoid. Moreover, suppression of
vasoactive intestinal peptide (VIP) expression alone induced
neuroblastoma cell differentiation, and VIP was up-regulated by TG2-L, but not TG2-S. Taken together, our data indicate that TG2-L and TG2-S exert opposite effects on cell differentiation due to differences in
GTP binding and modulation of VIP gene transcription. Our findings highlight the potential importance of repressing the
GTP binding activity of TG2-L or activating the transamidase activity of TG2-L or TG2-S for the treatment of
neuroblastoma, and possibly also other Myc-induced
malignancies, and for enhancing
retinoid anticancer effects.