Expression of Phosphorylated p27^Kip1Protein and Jun Activation Domain-Binding Protein 1 in Human Pituitary Tumors

Abstract

The cyclin-dependent kinase inhibitor p27(Kip1) (p27) plays a pivotal role in controlling cell proliferation during development and tumorigenesis. p27 has been implicated in pituitary tumorigenesis in studies of knockout mice and in analyses of human pituitary tumor samples. In this study, we further explored the role of p27 in human pituitary tumors by measuring levels of phosphorylated p27 (P-p27), and also Jun activation domain-binding protein 1 (Jab1), which is thought to facilitate the phosphorylation and degradation of p27, in normal pituitary tissue (n = 21), pituitary adenomas (n = 75), and pituitary carcinomas (n = 10). The amount of p27 protein in corticotroph adenomas and pituitary carcinomas was much lower than that in normal pituitary tissue or other types of pituitary adenoma. Nuclear P-p27 protein levels were significantly decreased in the adenomas, compared with the normals, and were much lower in the carcinomas, compared with either normal pituitary tissue or pituitary adenomas. However, P-p27 levels in corticotroph adenomas were similar to normal pituitary tissue, thus demonstrating a greatly increased ratio of P-p27 to p27 specifically in corticotroph tumors. No difference was found in Jab1 protein levels in either corticotroph tumors or other pituitary adenomas, compared with normal tissue, but there was a small but significant increase in Jab1 levels in carcinomas. Corticotroph and metastatic tumors both showed a significantly higher Ki-67 labeling index than normal pituitary or other types of pituitary adenomas, and in general the Ki-67 labeling index was negatively correlated with p27 nuclear staining. The amount of p27 and Jab1 mRNA was positively correlated in all pituitary samples studied but did not correlate with the changes in immunostaining. Our findings suggest that in corticotroph tumors there is an accentuated phosphorylation of p27 into P-p27, possibly related to increased cyclin E expression, whereas both p27 and P-p27 are subject to increased degradation in pituitary carcinomas. Such variations in phosphorylation may play a role in pituitary tumorigenesis, but modulation of Jab1 is unlikely to be important in the pathogenesis of pituitary adenomas.

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

“…0.05)) (19). The p27 staining was predominantly nuclear, as previously reported, and the occasional diffuse cytoplasmic staining did not reveal any further differences between the groups (20,21). We also studied the correlation between Ki-67 and p27 staining: in the octreotide-treated group this showed a negative trend with RZK0.4, PZ0.07.…”

“…We have shown previously that normal somatotroph cells contain more p27 protein than somatotroph adenoma cells: for example, 75% of somatotroph cells in the normal pituitary show positive immunostaining for p27, while somatotroph cells in adenomas show only 40% p27 staining (26). This staining is predominantly nuclear, where it is considered that p27 acts as a Cdk inhibitor to modulate cell proliferation.…”

Thioredoxin modulates activator protein 1 (AP-1) activity and p27Kip1 degradation through direct interaction with Jab1

“…Very recently, elevated Jab1 expression was reported in human pituitary tumors (Korbonits et al, 2002), epithelial ovarian cancer (Sui et al, 2001), breast cancer (Kouvaraki et al, 2003), and some types of lymphoma (Ito et al, 2003;Rassidakis et al, 2003). In these cases, the Jab1 levels were inversely associated with p27Kip1 levels and positively correlated with disease progression.…”

“…Taken together, these observations suggest that Jab1 may play an important role in human oncogenesis. Interestingly, overexpression of Jab1 has been correlated with aggressiveness or inferior overall survival in human pituitary tumors (Korbonits et al, 2002), epithelial ovarian cancer (Sui et al, 2001), breast cancer (Kouvaraki et al, 2003), and some types of lymphoma (Ito et al, 2003;Rassidakis et al, 2003). These findings suggest that the increased malignancy may be due to pleiotropic phenotypes resulting from Jab1 overexpression, such as decreased levels of p27, upregulation of AP-1 transcriptional activity, and CSNmediated phosphorylation of various transcription regulators.…”

15 YEARS OF PARAGANGLIOMA: The association of pituitary adenomas and phaeochromocytomas or paragangliomas

“…Kip1 (Pellegata et al 2006), a tumour suppressor previously implicated in pituitary tumorigenesis in knockout mice (Nakayama et al 1996) and known to be downregulated in human pituitary adenomas (Lidhar et al 1999, Korbonits et al 2002. A pathogenic truncating mutation in the human orthologue CDKN1B was identified in a 48-year-old woman with a personal history of acromegaly and primary hyperparathyroidism and a family history of renal Printed in Great Britain angiomyolipoma in a confirmed mutation carrier (Pellegata et al 2006).…”