title: Differential regulation of cyclin-dependent kinase inhibitors in neuroblastoma cells.
abstract: Gastrin-releasing peptide (GRP) and its receptor (GRP-R) are highly expressed in undifferentiated neuroblastoma, and they play critical roles in oncogenesis. We previously reported that GRP activates the PI3K/AKT signaling pathway to promote DNA synthesis and cell cycle progression in neuroblastoma cells. Conversely, GRP-R silencing induces cell cycle arrest. Here, we speculated that GRP/GRP-R signaling induces neuroblastoma cell proliferation via regulation of cyclin-dependent kinase (CDK) inhibitors. Surprisingly, we found that GRP/GRP-R differentially induced expressions of p21 and p27. Silencing GRP/GRP-R decreased p21, but it increased p27 expressions in neuroblastoma cells. Furthermore, we found that the intracellular localization of p21 and p27 in the nuclear and cytoplasmic compartments, respectively. In addition, we found that GRP/GRP-R silencing increased the expression and accumulation of PTEN in the cytoplasm of neuroblastoma cells where it co-localized with p27, thus suggesting that p27 promotes the function of PTEN as a tumor suppressor by stabilizing PTEN in the cytoplasm. GRP/GRP-R regulation of CDK inhibitors and tumor suppressor PTEN may be critical for tumoriogenesis of neuroblastoma.
authors.affiliation: Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Qiao
authors.forename: Pritha
authors.initials: P
authors.lastname: Paul
authors.forename: Sora
authors.initials: S
authors.lastname: Lee
authors.forename: Jingbo
authors.initials: J
authors.lastname: Qiao
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Dai H
authors.initials: DH
authors.lastname: Chung
mesh_terms: D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D019886:Gastrin-Releasing Peptide / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009447:Neuroblastoma / Q000201:enzymology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D018004:Receptors, Bombesin / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018004:Receptors, Bombesin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019886:Gastrin-Releasing Peptide; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human