CDK5 and Its Activator P35 in Normal Pituitary and in Pituitary Adenomas: Relationship to VEGF Expression

Abstract

Pituitary tumors are monoclonal adenomas that account for about 10-15% of intracranial tumors. Cyclin-dependent kinase 5 (CDK5) regulates the activities of various proteins and cellular processes in the nervous system, but its potential roles in pituitary adenomas are poorly understood. The kinase activity of CDK5 requires association with an activating protein, p35 (also known as CDK5 activator 1, p35). Here, we show that functional CDK5, associated with p35, is present in normal human pituitary and in pituitary tumors. Furthermore, p35 mRNA and protein levels were higher in pituitary adenomas than in the normal glands, suggesting that CDK5 activity might be upregulated in pituitary tumors. Inhibition of CDK5 activity in rat pituitary cells, reduced the expression of vascular endothelial growth factor (VEGF), a protein that regulates vasculogenesis and angiogenesis. Our results suggest that increased CDK5-mediated VEGF expression might play a crucial role in the development of pituitary adenomas, and that roscovitine and other CDK5 inhibitors could be useful as anticancer agents.

Phosphorylation of kinase insert domain receptor by cyclin-dependent kinase 5 at serine 229 is associated with invasive behavior and poor prognosis in prolactin pituitary adenomas

“…The functional role of CDK5 activity in cell proliferation, migration, and invasiveness of pituitary adenoma cells remains to be elucidated. In our previous study [7], we found that active CDK5 was present in normal pituitary cells, associated with p35, and that CDK5 activity was upregulated in pituitary adenomas. CDK5 has also been shown to regulate angiogenesis and the migration of endothelial cells, and has been proposed as a target for antiangiogenic therapy [28].…”

“…Recently, CDK5 has been demonstrated to be involved in pancreatic [26], lung, and prostate [27] cancer. Although the in vitro and in vivo expression profiles of CDK5 have been investigated in several types of cancer, no published data on the expression and function of CDK5 in prolactin pituitary adenomas are available except for a report by Xie et al [7]. The functional role of CDK5 activity in cell proliferation, migration, and invasiveness of pituitary adenoma cells remains to be elucidated.…”

“…Liu et al have also reported that increased CDK5 expression in patients with non-small cell lung cancer is correlated with poor prognosis [6]. Previously, we have found that active CDK5 was present in normal human pituitary tissue, was associated with p35, and that CDK5 activity was upregulated in diverse types of pituitary adenomas [7], suggesting CDK5 activity may play a role in pituitary tumor progression. A better understanding of cellular and molecular mechanisms mediated by CDK5 may provide a therapeutic strategy for pituitary tumors.…”

Phosphorylation of Pit-1 by Cyclin-Dependent Kinase 5 at Serine 126 is Associated with Cell Proliferation and Poor Prognosis in Prolactinomas

“…Although CDK5 has been investigated in some types of cancers, the functional role of CDK5 in proliferation and apoptosis of pituitary adenoma cells remains to be elucidated. In our previous study (13,14,21), we found that CDK5 activity was upregulated in pituitary adenomas and was associated with p35. Here, we have shown that both proliferation and apoptosis of pituitary cells were regulated by pSer126-Pit-1.…”

“…CDK5 is not activated by cyclins but by its activators p35 and p39 (11,12), whose constitutive expression is largely restricted to cells of neural crest origin. Our group found for the rst time that CDK5 exists in normal human pituitary and pituitary adenomas and found that CDK5 can promote the growth and invasion of pituitary adenomas (13,14), but the true regulatory mechanism of CDK5 in pituitary tumors is far from clear; speci cally, it is unknown whether CDK5 is involved in the regulation of hormone synthesis, secretion, and apoptosis in prolactinoma, which requires in-depth research.…”