Neurofibromatosis 1 (NF1) heterozygosity results in a cell-autonomous growth advantage for astrocytes

Bajenaru, M. L.; Donahoe, Jessica; Corral, Teresa; Reilly, Karlyne M.; Brophy, Sean; Pellicer, Ángel Antonio Blasco; Gutmann, David H.

doi:10.1002/1098-1136(20010315)33:4<314::aid-glia1030>3.0.co;2-q

Cited by 72 publications

(62 citation statements)

References 39 publications

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“…Previous experiments on mice heterozygous for a targeted defect in the neuro®bromatosis 1 (Nf1) gene have demonstrated signi®cant genetic cooperativity between Nf1 and p53 (Bajenaru et al, 2001). This genetic cooperativity between Nf1+/7;p53+/7 mice was also re¯ected in malignant tumor formation (Reilly et al, 2000).…”

Section: Discussioncontrasting

confidence: 99%

“…Based on previous work on the Nf1 tumor suppressor gene (Bajenaru et al, 2001), we explored the possibility that mice doubly heterozygous for Tsc2 and p53 would also exhibit cooperativity to increase astrocyte numbers in vivo. Whereas both Tsc2+/7 and p53+/7 mice demonstrate a 50% increase in the number of GFAP-immunoreactive astrocytes in the CA1 region of the hippocampus, no further increases were observed in the Tsc2+/7;p53+/7 mice ( Figure 4b).…”

Section: Resultsmentioning

confidence: 99%

“…In contrast with our previous experiments on Nf1+/7 astrocytes (Bajenaru et al, 2001), we observed no di erences in Tsc2+/7 astrocyte growth in vitro. It is possible that our experiments did not provide the correct cellular context in which to maximize the potential di erences in astrocyte growth between Tsc2+/7 and wild type astrocytes.…”

Section: Discussionmentioning

confidence: 99%

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Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/− cells

et al. 2002

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Section: Discussioncontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/− cells

et al. 2002

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“…CDK4 overexpression provides a small astrocyte growth advantage in vivo, but not in vitro To investigate whether the overexpression of CDK4 in astrocytes provides a growth advantage in vivo, we determined the number of GFAP-immunoreactive cells (astrocytes) in the hippocampus using previously established approaches employed in our analysis of Nf1+/7 mice Bajenaru et al, 2001). GFAP-hCDK4 mice exhibit a slight increase in astrocyte number (21 ± 26% increase) compared to the wild-type littermates ( Figure 3).…”

Section: Generation and Identification Of Astrocyte-specific Cdk4 Tramentioning

confidence: 99%

“…Approximately 15 ± 20% of children with neuro®bro-matosis 1 (NF1) develop low-grade astrocytomas (Listernick et al, 1999) resulting from loss of the NF1 tumor suppressor, neuro®bromin, which functions as a negative regulator of RAS . Inactivation of NF1 in these astrocytic tumors results in increased RAS pathway activation and provides a growth advantage for astrocytes in vitro and in vivo (Bajenaru et al, 2001;Gutmann et al, 1999). Similarly, individuals with LFS develop astrocytomas as a result of an inherited mutation in the p53 tumor suppressor gene (Li and Fraumeni, 1969;Bischo et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2002

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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 ampli®ca-tion of cyclin dependent kinase-4 (CDK4). To de®ne the function of CDK4 ampli®cation/overexpression in astrocytoma pathogenesis, we generated three transgenic mouse lines that overexpress human CDK4 (hCDK4) in astrocytes using the human glial ®brillary 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+/ 7 as well as p53+/7; Rb+/7 mice exhibited increased numbers of astrocytes compared to GFAP-hCDK4, p53+/7, or Rb+/7 mice in vivo. No cooperative e ect was observed with GFAP-hCDK4; Rb+/7 mice. These results support the hypothesis that cdk4 overexpression alone is not su cient for astrocytoma formation, but can provide a cooperative growth advantage in concert with genetic alterations in the p53 pathway.

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Outcomes of systematic screening for optic pathway tumors in children with Neurofibromatosis Type 1

Blazo

Lewis

Chintagumpala

et al. 2004

American J of Med Genetics Pt A

100

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Optic pathway tumors (OPT) occur in about 15% of individuals with Neurofibromatosis Type 1 (NF1) and may effect substantial visual loss. Because their growth is not predictable at the time of discovery, neuroimaging for OPT in asymptomatic NF1 patients remains controversial. We evaluated the outcomes of systematic screening by both MRI and ophthalmic examinations for OPT in young children with NF1 seen at multi-disciplinary clinics for Neurofibromatosis and Genetics at one institution between 1996 and 2001. We report on 84 children who presented with NF1 under age 6 years, of whom 13 children presented with either known OPT or abnormal MRI findings and 11 children had OPTs identified by neuroimaging, including two children with abnormal eye examinations at presentation (one with strabismus and one with optic atrophy). Nine OPTs were detected in asymptomatic subjects with normal ophthalmic examinations. Three children with chiasmal lesions enlarging on subsequent MRI were treated with carboplatin and vincristine. After treatment, the vision in each involved eye was intact. In contrast, the 13 children with OPT diagnosed outside of screening guidelines included five children with substantial visual loss. Our observations suggest that early recognition of NF1 promotes appropriate surveillance and allows early intervention to reduce complications of OPT. This analysis supports prospective studies to compare the outcomes of systematic screening with neuroimaging to screening with ophthalmic examinations alone in children with NF1.

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Neurofibromatosis 1 (NF1) heterozygosity results in a cell-autonomous growth advantage for astrocytes

Cited by 72 publications

References 39 publications

Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/− cells

Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/− cells

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

Outcomes of systematic screening for optic pathway tumors in children with Neurofibromatosis Type 1

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