3 results on '"Gershon TR"'
Search Results
2. ASC deficiency suppresses proliferation and prevents medulloblastoma incidence.
- Author
-
Knight ER, Patel EY, Flowers CA, Crowther AJ, Ting JP, Miller CR, Gershon TR, and Deshmukh M
- Subjects
- Adolescent, Adult, Animals, Apoptosis Regulatory Proteins deficiency, CARD Signaling Adaptor Proteins, Cerebellar Neoplasms metabolism, Cerebellar Neoplasms pathology, Child, Child, Preschool, Cytoskeletal Proteins genetics, Cytoskeletal Proteins metabolism, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, In Situ Hybridization, Infant, Male, Medulloblastoma metabolism, Medulloblastoma pathology, Mice, Knockout, Mice, Transgenic, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction genetics, Transforming Growth Factor beta genetics, Transforming Growth Factor beta metabolism, Young Adult, Apoptosis Regulatory Proteins genetics, Cell Proliferation, Cerebellar Neoplasms genetics, Medulloblastoma genetics
- Abstract
Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC's role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer; ASC is also expressed in human medulloblastomas. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knockout mice on the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and a delayed tumor onset. A similar decrease in tumorigenesis with ASC deficiency was also seen in the hGFAP-Cre:SmoM2 mouse model of medulloblastoma. Interestingly, hyperproliferation of the external granule layer (EGL) was comparable at P20 in both wild-type and ASC-deficient SmoA1 mice. However, while the apoptosis and differentiation markers remained unchanged at this age, proliferation makers were decreased, and the EGL was reduced in thickness and area by P60. This reduction in proliferation with ASC deficiency was also seen in isolated SmoA1 cerebellar granule precursor cells in vitro, indicating that the effect of ASC deletion on proliferation was cell autonomous. Interestingly, ASC-deficient SmoA1 cerebella exhibited disrupted expression of genes in the transforming growth factor-β pathway and increased level of nuclear Smad3. Taken together, these results demonstrate an unexpected role for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for antitumor therapy.
- Published
- 2015
- Full Text
- View/download PDF
3. Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation.
- Author
-
Garcia I, Crowther AJ, Gama V, Miller CR, Deshmukh M, and Gershon TR
- Subjects
- Animals, Apoptosis genetics, Cell Differentiation genetics, Cell Movement genetics, Cerebellar Neoplasms metabolism, Cerebellum cytology, Cerebellum metabolism, Cerebellum pathology, Down-Regulation, Medulloblastoma metabolism, Mice, Mice, Transgenic, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Smoothened Receptor, Stem Cells metabolism, bcl-2-Associated X Protein metabolism, Cerebellar Neoplasms genetics, Cerebellar Neoplasms pathology, Medulloblastoma genetics, Medulloblastoma pathology, Neurogenesis genetics, bcl-2-Associated X Protein genetics
- Abstract
Neurogenesis requires negative regulation through differentiation of progenitors or their programmed cell death (PCD). Growth regulation is particularly important in the postnatal cerebellum, where excessive progenitor proliferation promotes medulloblastoma, the most common malignant brain tumor in children. We present evidence that PCD operates alongside differentiation to regulate cerebellar granule neuron progenitors (CGNPs) and to prevent medulloblastoma. Here, we show that genetic deletion of pro-apoptotic Bax disrupts regulation of cerebellar neurogenesis and promotes medulloblastoma formation. In Bax(-/-) mice, the period of neurogenesis was extended into the third week of postnatal life, and ectopic neurons and progenitors collected in the molecular layer of the cerebellum and adjacent tectum. Importantly, genetic deletion of Bax in medulloblastoma-prone ND2:SmoA1 transgenic mice greatly accelerated tumorigenesis. Bax-deficient medulloblastomas exhibited strikingly distinct pathology, with reduced apoptosis, increased neural differentiation and tectal migration. Comparing Bax(+/+) and Bax(-/-) medulloblastomas, we were able to identify upregulation of Bcl-2 and nuclear exclusion of p27 as tumorigenic changes that are required to mitigate the tumor suppressive effect of Bax. Studies on human tumors confirmed the importance of modulating Bax in medulloblastoma pathogenesis. Our results demonstrate that Bax-dependent apoptosis regulates postnatal cerebellar neurogenesis, suppresses medulloblastoma formation and imposes selective pressure on tumors that form. Functional resistance to Bax-mediated apoptosis, required for medulloblastoma tumorigenesis, may be a tumor-specific vulnerability to be exploited for therapeutic benefit.
- Published
- 2013
- Full Text
- View/download PDF
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