Phosphatidylinositol 3'-kinase, mTOR, and glycogen synthase kinase-3β mediated regulation of p21 in human urothelial carcinoma cells.

Background: The PTEN/Phosphatidylinositol 3'-kinase (PI3-kinase) growth factor signaling pathway plays a critical role in epithelial tumor development in a multitude of tissue types. Deletion of the Pten tumor suppressor gene in murine urothelial cells in vivo results in upregulation of cyclin-dependent kinase inhibitor p21. We have previously shown in mice that p21 expression blocks an increase in urothelial cell proliferation due to Pten deletion.

Pten deficiency activates distinct downstream signaling pathways in a tissue-specific manner.

PTEN deficiency predisposes to a subset of human cancers, but the mechanism that underlies such selectivity is unknown. We have generated a mouse line that conditionally deletes Pten in urogenital epithelium. These mice develop carcinomas at high frequency in the prostate but at relatively low frequency in the bladder, despite early and complete penetrance of hyperplasia in both organs.

Deletion of Epstein-Barr virus regulatory sequences upstream of the EBNA gene promoter Wp1 is unfavorable for B-Cell immortalization.

Transcription of the six Epstein-Barr virus (EBV) EBNA genes is coordinately regulated, being driven by either the Cp promoter, which is encoded within the unique region just upstream of the EBV major internal repeat (IR-1), or by the Wp promoter, which is encoded within the IR-1 repeat and thus present in multiple copies. Previous analyses of Cp- and Wp-initiated transcription have identified a shared cis-regulatory element mapping to the region extending from -169 to -369 bp upstream of the Wp transcription initiation site (M. T.