title: Astrocyte-specific expression of CDK4 is not sufficient for tumor formation, but cooperates with p53 heterozygosity to provide a growth advantage for astrocytes in vivo.
abstract: The development of malignant gliomas (astrocytomas) involves the accumulation of multiple genetic changes, including mutations in the p53 and retinoblastoma (Rb) cell cycle regulatory pathways. One Rb pathway alteration seen in high-grade astrocytomas is amplification of cyclin dependent kinase-4 (CDK4). To define the function of CDK4 amplification/overexpression in astrocytoma pathogenesis, we generated three transgenic mouse lines that overexpress human CDK4 (hCDK4) in astrocytes using the human glial fibrillary acidic protein (GFAP) promoter. GFAP-hCDK4 mice do not develop brain tumors, but exhibit a small increase in astrocyte number. Cultured astrocytes from these mice do not demonstrate a cell-autonomous growth advantage in vitro and lack properties of transformed cells. To determine whether cdk4 overexpression provides a cooperative growth advantage in vitro, CDK4-overexpressing C6 glioma cell lines were generated and found to exhibit increased cell growth. In addition, GFAP-hCDK4; p53+/- as well as p53+/-; Rb+/- mice exhibited increased numbers of astrocytes compared to GFAP-hCDK4, p53+/-, or Rb+/- mice in vivo. No cooperative effect was observed with GFAP-hCDK4; Rb+/- mice. These results support the hypothesis that cdk4 overexpression alone is not sufficient for astrocytoma formation, but can provide a cooperative growth advantage in concert with genetic alterations in the p53 pathway.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri, MO 63110, USA.
authors.forename: Zhi-yong
authors.initials: ZY
authors.lastname: Huang
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Baldwin
authors.forename: Nicolé M
authors.initials: NM
authors.lastname: Hedrick
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D001254:Astrocytoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005910:Glioma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D011518:Proto-Oncogene Proteins; D051381:Rats; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C495902:Cdk4 protein, mouse; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases