Down-regulation of the diphthamide biosynthesis protein 2-like gene duringretinoid-induced differentiation and apoptosis, implications against its tumor-suppressor activity

Retinoids, synthetic and natural analogs of retinoic acid (RA) have profoun d effects on the proliferation and differentiation of many cell types; this accounts for their beneficial effects in the treatment of certain neoplasi as. We have employed mRNA differential display to characterize genes associ ated with differentiation and apoptosis induced by all-trans RA in human lu ng cancer cells, We have identified a cDNA corresponding to the sequence of the known gene diphthamide biosynthesis protein 2-like (DPH2L), Although t he function of this gene remains unknown, as it was first isolated from the critical region of deletion on chromosome 17p13.3 in human ovarian carcino ma, it has been regarded as a candidate tumor-suppressor gene. In this repo rt, we provide evidence chat DPH2L is down-regulated during differentiation or apoptosis in several cancer cell lines after treatment with all-trans R A or N-(4-hydroxyphenyl)retinamide and during cell-cycle arrest, Moreover, stable expression of DPH2L-specific anti-sense construct leads to inhibitio n of cell proliferation. Our results suggest that DPH2L in not a convention al tumor-suppressor gene. Instead, it may be a growth regulator and its dow n-regulation might be permissive for the transition from cell growth to dif ferentiation or apoptosis, DPH2L might be a useful tool in the prognosis of neoplastic diseases. Int. J. Cancer 88:356-362, 2000, (C) 2000 Wiley-Liss, Inc.