Down-regulation of the Diphthamide biosynthesis protein 2-like gene during retinoid-induced differentiation and apoptosis: implications against its tumor-suppressor activity.
Retinoids, synthetic and natural analogs of retinoic acid (RA) have profound effects on the proliferation and differentiation of many cell types; this accounts for their beneficial effects in the treatment of certain neoplasias. We have employed mRNA differential display to characterize genes associated with differentiation and apoptosis induced by all-trans RA in human lung cancer cells. We have identified a cDNA corresponding to the sequence of the known gene diphthamide biosynthesis protein 2-like (DPH2L). Although the function of this gene remains unknown, as it was first isolated from the critical region of deletion on chromosome 17p13.3 in human ovarian carcinoma, it has been regarded as a candidate tumor-suppressor gene. In this report, we provide evidence that DPH2L is down-regulated during differentiation or apoptosis in several cancer cell lines after treatment with all-trans RA or N-(4-hydroxyphenyl)retinamide and during cell-cycle arrest. Moreover, stable expression of DPH2L-specific anti-sense construct leads to inhibition of cell proliferation. Our results suggest that DPH2L in not a conventional tumor-suppressor gene. Instead, it may be a growth regulator and its down-regulation might be permissive for the transition from cell growth to differentiation or apoptosis. DPH2L might be a useful tool in the prognosis of neoplastic diseases.
Liu
G
G
Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Wu
M
M
Levi
G
G
Ferrari
N
N
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018076:DNA, Complementary / Q000096:biosynthesis*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D012176:Retinoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018076:DNA, Complementary; D012176:Retinoids; D000246:Adenosine Diphosphate Ribose