Identification of Growth Arrest and DNA-Damage-Inducible Gene β (GADD45β) as a Novel Tumor Suppressor in Pituitary Gonadotrope Tumors

• Published in: Endocrinology (Philadelphia) 2011-10, Vol.152 (10), p.3603-3613
• Main Authors: Michaelis, Katherine A, Knox, Aaron J, Xu, Mei, Kiseljak-Vassiliades, Katja, Edwards, Michael G, Geraci, Mark, Kleinschmidt-DeMasters, B. K, Lillehei, Kevin O, Wierman, Margaret E
• Format: Article
• Language: English
• Subjects: Adult; Agar; Aged; Aged, 80 and over; Animals; Antigens, Differentiation - genetics; Antigens, Differentiation - physiology; Apoptosis; Autopsies; Autopsy; Bioinformatics; Biological and medical sciences; Bisulfite; Brain tumors; Cancer-Oncogenes; Cell Line; Cell proliferation; Colonies; Damage detection; Deoxyribonucleic acid; DNA; DNA Damage; Female; Fundamental and applied biological sciences. Psychology; GADD45 protein; Gadd45A protein; Genes, p53; Gonadotrophs - pathology; Growth factors; GTP-binding protein; Humans; Hypogonadism; Male; Mice; Middle Aged; Morbidity; Null cells; Oligonucleotide Array Sequence Analysis; p53 Protein; Pituitary; Pituitary (anterior); Pituitary Neoplasms - pathology; Promoters; Radiation damage; Surgery; Survival; Tumor cells; Tumor suppressor genes; Tumor Suppressor Proteins - physiology; Tumorigenesis; Tumors; Vertebrates: endocrinology; Visual effects
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2011-0109

Gonadotrope and null cell pituitary tumors cause significant morbidity, often presenting with signs of hypogonadism together with visual disturbances due to mass effects. Surgery and radiation are the only therapeutic options to date. To identify dysregulated genes and pathways that may play a role in tumorigenesis and/or progression, molecular profiling was performed on 14 gonadotrope tumors, with nine normal human pituitaries obtained at autopsy serving as controls. Bioinformatic analysis identified putative downstream effectors of tumor protein 53 (p53) that were consistently repressed in gonadotrope pituitary tumors, including RPRM, P21, and PMAIP1, with concomitant inhibition of the upstream p53 regulator, PLAGL1(Zac1). Further analysis of the growth arrest and DNA damage-inducible (GADD45) family revealed no change in the p53 target, GADD45α, but identified repression of GADD45β in pituitary tumors in addition to the previously reported inhibition of GADD45γ. Overexpression of GADD45β in LβT2 mouse gonadotrope cells blocked tumor cell proliferation and increased rates of apoptosis in response to growth factor withdrawal. Stable gonadotrope cell transfectants expressing increased GADD45β showed decreased colony formation in soft agar, confirming its normal role as a tumor suppressor. Unlike previous studies of GADD45γ in pituitary tumors and α and β in other tumors, bisulfite sequencing showed no evidence of hypermethylation of the GADD45β promoter in human pituitary tumor samples to explain the repression of its expression. Thus, GADD45β is a novel pituitary tumor suppressor whose reexpression blocks proliferation, survival, and tumorigenesis. Together these studies identify new targets and mechanisms to explore in pituitary tumor initiation and progression.