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

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.

Spatial and temporal expression of immunoglobulin superfamily member 1 in the rat

“…IGSF1 expression was observed in thyrotropes, somatotropes, and lactotropes, but not gonadotropes (Sun et al 2012), which is consistent with our results in the adult rat. However, increased amounts of Igsf1 mRNA have been observed in pituitary adenoma secreting GH or prolactin, while decreased amounts were observed in those secreting ACTH or gonadotropins (NCBI GEO profiles ID 11104016 (Morris et al 2005), 83167537 (Michaelis et al 2011)), in accordance with the PIT1 lineage.…”

Pituitary adenoma: a literature review

“…Mi cha e lis ir au to riai nu sta të, kad GADD45a eks pre si ja be veik ne si sky rë svei kø ir ser ganèiø HA or ga niz muo se, o GADD45b eks pre si ja, ser gant ðiuo na vi ku, bu vo su ma þë ju si. Ta èiau pro mo to riaus me ti -li ni mas ne bu vo ap tik tas, tai gi prie þas tis lie ka ne aið ki [35].…”

“…P53 yra ga lin gas transk rip ci jos fakto rius, re gu liuo jan tis tu mo ro su pre so riø ge nø funk ci jas, pa vyz dþiui, DNR re pa ra ci jà, làs te lës cik lo ir da li ni mo si stab dy mà, se në ji mà ir apop to zae [23]. TP53 yra vie nas labiau siai inak ty vuo ja mø ge nø ávai riø na vi kø pa to genezëje, ta èiau HA at ve ju tai ste bi ma re tai, daþ niau jas su kelia p53 kas ka do je da ly vau jan tys ge nai ir jø pro duk tai [23,35].…”

MANAGEMENT OF ENDOCRINE DISEASE: Clinicopathological classification and molecular markers of pituitary tumours for personalized therapeutic strategies

“…With the exception of GADD45g (GADD45G), characterised by Zhang et al (70), the functional involvement of the majority of these genes in pituitary tumour pathogenesis remains to be determined. Indeed, GADD45 (GADD45A) expression has been extensively studied by independent groups (70,71,72,73); all of which demonstrated that the down-regulation of GADD45g is more frequently found in non-functioning pituitary adenomas (NFPAs) than in functioning tumours (90 and 58% respectively) ((74, 75) for review), and that promoter methylation seems to be the major cause of loss of GADD45 expression in pituitary tumours (71).…”