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Loss of Arf causes ...
Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma
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- Tchougounova, Elena (author)
- Uppsala universitet,Institutionen för genetik och patologi
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- Kastemar, Marianne (author)
- Uppsala universitet,Institutionen för genetik och patologi
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- Bråsäter, Daniel (author)
- Uppsala universitet,Institutionen för genetik och patologi,Ludwiginstitutet för cancerforskning
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Holland, E C (author)
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- Westermark, Bengt (author)
- Uppsala universitet,Institutionen för genetik och patologi
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- Uhrbom, Lene (author)
- Uppsala universitet,Institutionen för genetik och patologi
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(creator_code:org_t)
- 2007-04-16
- 2007
- English.
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In: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 26:43, s. 6289-6296
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Abstract
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- In a subset of gliomas, the platelet-derived growth factor (PDGF) signaling pathway is perturbed. This is usually an early event occurring in low-grade tumors. In high-grade gliomas, the subsequent loss of the INK4a-ARF locus is one of the most common mutations. Here, we dissected the separate roles of Ink4a and Arf in PDGFB-induced oligodendroglioma development in mice. We found that there were differential functions of the two tumor suppressor genes. In tumors induced from astrocytes, both Ink4a-loss and Arf-loss caused a significantly increased incidence compared to wild-type mice. In tumors induced from glial progenitor cells there was a slight increase in tumor incidence in Ink4a-/- mice and Ink4a-Arf-/- mice compared to wild-type mice. In both progenitor cells and astrocytes, Arf-loss caused a pronounced increase in tumor malignancy compared to Ink4a-loss. Hence, Ink4a-loss contributed to tumor initiation from astrocytes and Arf-loss caused tumor progression from both glial progenitor cells and astrocytes. Results from in vitro studies on primary brain cell cultures suggested that the PDGFB-induced activation of the mitogen-activated protein kinase pathway via extracellular signal-regulated kinase was involved in the initiation of low-grade oligodendrogliomas and that the additional loss of Arf may contribute to tumor progression through increased levels of cyclin D1 and a phosphoinositide 3-kinase-dependent activation of p70 ribosomal S6 kinase causing a strong proliferative response of tumor cells.
Keyword
- oligodendroglioma
- PDGF
- mouse model
- Ink4a
- Arf
- p70S6K
- MEDICINE
- MEDICIN
Publication and Content Type
- ref (subject category)
- art (subject category)
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