Identification of growth arrest and DNA-damage- inducible gene β (GADD45β) as a novel tumor suppressor in pituitary gonadotrope tumors

Katherine A. Michaelis, Aaron J. Knox, Mei Xu, Katja Kiseljak-Vassiliades, Michael G. Edwards, Mark Geraci, B. K. Kleinschmidt-DeMasters, Kevin O. Lillehei, Margaret E. Wierman

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3603-3613
Number of pages11
JournalEndocrinology
Volume152
Issue number10
DOIs
StatePublished - Oct 2011
Externally publishedYes

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Pituitary Neoplasms
DNA Damage
Growth
Genes
Neoplasms
Carcinogenesis
Null Lymphocytes
Proteins
Hypogonadism
Computational Biology
Agar
Autopsy
Intercellular Signaling Peptides and Proteins
Cell Proliferation
Radiation
Apoptosis
Morbidity
Survival

ASJC Scopus subject areas

  • Endocrinology

Cite this

Michaelis, K. A., Knox, A. J., Xu, M., Kiseljak-Vassiliades, K., Edwards, M. G., Geraci, M., ... Wierman, M. E. (2011). Identification of growth arrest and DNA-damage- inducible gene β (GADD45β) as a novel tumor suppressor in pituitary gonadotrope tumors. Endocrinology, 152(10), 3603-3613. https://doi.org/10.1210/en.2011-0109

Identification of growth arrest and DNA-damage- inducible gene β (GADD45β) as a novel tumor suppressor in pituitary gonadotrope tumors. / 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.

In: Endocrinology, Vol. 152, No. 10, 10.2011, p. 3603-3613.

Research output: Contribution to journalArticle

Michaelis, KA, Knox, AJ, Xu, M, Kiseljak-Vassiliades, K, Edwards, MG, Geraci, M, Kleinschmidt-DeMasters, BK, Lillehei, KO & Wierman, ME 2011, 'Identification of growth arrest and DNA-damage- inducible gene β (GADD45β) as a novel tumor suppressor in pituitary gonadotrope tumors', Endocrinology, vol. 152, no. 10, pp. 3603-3613. https://doi.org/10.1210/en.2011-0109
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. / Identification of growth arrest and DNA-damage- inducible gene β (GADD45β) as a novel tumor suppressor in pituitary gonadotrope tumors. In: Endocrinology. 2011 ; Vol. 152, No. 10. pp. 3603-3613.
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