Identification of an Amplified, Highly Expressed Gene in a Human Glioma

Kinzler, Kenneth W.; Bigner, Sandra H.; Bigner, Darrell D.; Trent, Jeffrey M.; Law, Martha Liao; O’Brien, Stephen J.; Wong, Albert J.; Vogelstein, Bert

doi:10.1126/science.3563490

Cited by 622 publications

(383 citation statements)

References 36 publications

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“…These ®ndings, together with the fact that the invertebrate developmental regulators tra-1 and ci are Gli homologues (Orenic et al, 1990;Zarkower and Hodgkin, 1993), indicates that the Gli proteins perform primary roles in cell growth and di erentiation. The association of enhanced Gli gene expression with numerous forms of cancer (Kinzler et al, 1987;Roberts et al, 1989) is also consistent with a critical role in regulating cell proliferation. The present ®ndings thus extend the implicated role for Gli genes in developing cells to spermatogenesis as well.…”

Section: Discussionmentioning

confidence: 75%

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Gli family members are differentially expressed during the mitotic phase of spermatogenesis

et al. 1997

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The Gli family of DNA binding proteins has been implicated in multiple neoplasias and developmental abnormalities, suggesting a primary involvement in cell development and di erentiation. However, to date their speci®c roles and mechanisms of action remain obscure, and a drawback has been the lack of a model system in which to study their normal function. Here we demonstrate that Gli family members are di erentially expressed during spermatogenesis in mice. Speci®cally, Gli and Gli3 mRNAs were detected in mouse germ cells, while Gli2 was not. Further, both Gli and Gli3 exhibited stage-dependent patterns of expression selectively in type A and B spermatogonia. Gli expression was somewhat higher in type B spermatogonia while the abundance of Gli3 transcripts was similar in type A and B cells. Gel-shift analyses also demonstrated the enrichment of DNA binding activity speci®c for the Gli target sequence in spermatogonial cells. These results indicate a selective role for Gli and Gli3 during mitotic stages of male germ cell development. Spermatogenesis may thus provide a unique opportunity to identify downstream targets and explore the normal function of Gli family proteins.

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Section: Discussionmentioning

confidence: 75%

“…The Gli genes constitute a family of DNA binding proteins that have been implicated in several neoplasias, including glioblastoma (Kinzler et al, 1987;Roberts et al, 1989). Three distinct Gli genes have been identi®ed in human and mouse, Gli, Gli2, Gli3 Ruppert et al, 1988Ruppert et al, , 1990Vortkamp et al, 1992;Hui et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Gli family members are differentially expressed during the mitotic phase of spermatogenesis

et al. 1997

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“…Active Hedgehog-Gli signaling is also associated with gliomas (Shahi et al, 2008). In fact, the key intracellular mediator Gli was originally discovered in a glioma (Kinzler et al, 1987). Moreover, Gli activity correlates with tumor grade in a genetically engineered mouse model (Becher et al, 2008).…”

Section: Hedgehog-gli Signalingmentioning

confidence: 99%

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

et al. 2010

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Glioblastomas (GBMs) are highly lethal primary brain tumors. Despite current therapeutic advances in other solid cancers, the treatment of these malignant gliomas remains essentially palliative. GBMs are extremely resistant to conventional radiation and chemotherapies. We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells (GSCs) promotes therapeutic resistance. We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth, which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs. Furthermore, stem cell-like cancer cells (cancer stem cells) have been shown to promote metastasis. Although GBMs rarely metastasize beyond the central nervous system, these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection, and GSCs display an aggressive invasive phenotype. These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment. Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells, but also display critical distinctions that provide important clues into useful therapeutic targets. In this review, we summarize the current understanding and advances in glioma stem cell research, and discuss potential targeting strategies for future development of anti-GSC therapies.

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“…The result is to activate the Cubitus Interruptus (CI) zinc ®nger transcription factor, the human homologue is the oncogene GLI1 which then induces various target genes (Dominguez et al, 1996;Hepker et al, 1997;Kinzler et al, 1987Kinzler et al, , 1988. We have detected the expression of GLI3 (a putative negative transducer) in normal bladder as well as bladder carcinoma but we have been unable to detect GLI1 or GLI2 transcripts (data not shown).…”

Section: Discussionmentioning

confidence: 79%

PTCH gene mutations in invasive transitional cell carcinoma of the bladder

Tw¹,

Maruta²,

Je³

et al. 1998

Oncogene

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LOH analysis suggests that multiple tumor suppressor genes play a role in the development of human TCC. The human homolog of the Drosophila PTCH was recently cloned and mapped to the BCNS locus on 9q22.3, a chromosomal region commonly deleted in TCCs. We ®rst examined the steady state mRNA transcription of the PTCH, SMOH and GLI3 genes of the HH signal transduction pathway in TCC cell lines and normal urothelium. Normal urothelium and TCC cell lines express these three genes within the PTCH signal transduction pathway. We then screened for PTCH mutations in`hot spot' exons 6, 8, 13 and 16 by PCR/ SSCP analysis of genomic DNAs from 54 TCC tumor samples and control autologous peripheral blood lymphocytes. DNA sequence analysis con®rmed TCCspeci®c mutations in two of 54 patients (3.7%). These mutations resulted a single amino acid substitution and two frame shifts. One tumor had PTCH mutations in exon 16 as well as exon 13 and one tumor had a mutation in exon 13 alone. Both TCC tumors that contained PTCH mutations had a loss of heterozygosity at 9q. Although the PTCH protein has an unknown function in urothelial cells, the detection of the PTCH, SMOH and GLI3 transcripts in normal urothelium and TCC cell lines and rare PTCH mutations in tumor samples suggest that the HH pathway may have a role in controlling the proliferation of urothelial cells and that PTCH mutations may contribute to the development of a subset of TCCs.

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Identification of an Amplified, Highly Expressed Gene in a Human Glioma

Cited by 622 publications

References 36 publications

Gli family members are differentially expressed during the mitotic phase of spermatogenesis

Gli family members are differentially expressed during the mitotic phase of spermatogenesis

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

PTCH gene mutations in invasive transitional cell carcinoma of the bladder

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