Two groups of prolactinomas were identified, one slowly proliferating and responsive to bromocriptine and one fast-proliferating and bromocriptine-resistant. Nerve growth factor (NGF) inhibits proliferation of bromocriptine-resistant cells by still unclear mechanisms.

The tumor suppressor p53 is one of the key regulators of cell proliferation and in most tumors, but not pituitary adenomas, it is inactivated by genomic mutations. Here we investigated whether in prolactinoma cell lines NGF influences cell cycle-related pathways involving p53. By using conformation-specific antibodies and immunocytochemistry we found that in bromocriptine-resistant cells p53 adopts a "mutant" conformation that precludes its nuclear translocation and transcriptional activity. NGF administration to these cells refolds p53 into "wild-type" tertiary structure, promotes its nuclear translocation and restores its DNA-binding activity as demonstrated by the transcriptional activation of p21^Cip1/WAF1 and the resulting down-regulation of different cyclins and cdk2. Inactivation of trkA, but not of p75^NTR, and wortmannin prevented NGF-induced p53 nuclear translocation. Thus in prolactinoma cells p53 is inactivated by conformational mutation and cytoplasmic segregation. This defect is reversible since NGF reconstitutes active p53 in these cells. This effect of NGF is exclusively mediated by trkA through activation of phosphatidylinositol-3-kinase and may be related to its growth-inhibitory action.