title: CASZ1 inhibits cell cycle progression in neuroblastoma by restoring pRb activity.
abstract: Dysregulation of cell cycle genes such as Cyclin D1 and Chk1 contributes to the undifferentiated phenotype of neuroblastoma (NB). CASZ1 functions as a tumor suppressor in NB; here we sought to determine how loss of CASZ1 contributes to cell cycle dysregulation in NB. CASZ1 restoration in NB cells delays NB cell cycle progression. The earliest changes occur within 8 h of CASZ1 restoration in SY5Y cells with a 2.8-fold increase in the level of p21, an inhibitor of Cdk2/4. By 16 h, there is a 40% decrease in the steady-state levels of Cdk6. Restoration of CASZ1 decreases Cdk2-dependent cyclins A and E protein levels and Cdk4/6-dependent Cyclin D1 protein levels. The restoration of CASZ1 resulted in a decrease in pRb phosphorylation and a significant reduction of E2F transcriptional activity. Subsequent to the changes in the G 1/S transition, induction of CASZ1 results in a decrease in Cyclin B levels and Cdc25c phosphatase levels, an upstream activator of the G 2/M regulator CyclinB:Cdk1. In addition, induction of CASZ1 results in a decrease in the levels of phospho-Chk1, a key M-phase regulatory kinase. Similar results were found in a NB cell line with MYCN amplification. Taken together, this study indicates that restoration of CASZ1 activates pRb in G 1 and inhibits the G 2/M regulators Cyclin B1 and Chk1, leading to a lengthening of NB cell cycle progression and a subsequent decrease in cell proliferation.
authors.affiliation: Pediatric Oncology Branch; National Cancer Institute; Bethesda, MD, USA.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Liu
authors.forename: Julieann
authors.initials: J
authors.lastname: Rader
authors.forename: Stanley
authors.initials: S
authors.lastname: He
authors.forename: Tanya
authors.initials: T
authors.lastname: Phung
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Thiele
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C511127:CASZ1 protein, human; C534699:CCNB1 protein, human; C530104:CCND1 protein, human; D019925:Cyclin A; D056744:Cyclin B1; D019927:Cyclin E; D004268:DNA-Binding Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D019938:Cyclin D1; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D054462:p21-Activated Kinases; D018844:Cyclin-Dependent Kinases
keywords: CASZ1; Cdk; Chk1; Cyclin; Rb; cell cycle; neuroblastoma; tumor suppressor
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