Brain cancer stem-like cell genesis from p53-deficient mouse astrocytes by oncogenic Ras |
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Authors: | Lee Joong-Seob Gil Jung-Eun Kim Jong-Hoon Kim Tae-Kyung Jin Xun Oh Se-Yeong Sohn Young-Woo Jeon Hye-Min Park Hyo-Jung Park Jong-Whi Shin Yong-Jae Chung Yong Gu Lee Jang-Bo You Seungkwon Kim Hyunggee |
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Institution: | a Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Anam-dong, Seongbuk-gu, Seoul 136-713, Republic of Korea b Department of Pharmacology, School of Medicine, Korea University, Seoul, Republic of Korea c Department of Neurosurgery, School of Medicine, Korea University, Seoul, Republic of Korea |
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Abstract: | Here, we show that H-rasV12 causes the p53-knockout mouse astrocytes (p53−/− astrocytes) to be transformed into brain cancer stem-like cells. H-rasV12 triggers the p53−/− astrocytes to express a Nestin and a Cd133, which are expressed in normal and cancer neural stem cells. H-rasV12 also induces the formation of a single cell-derived neurosphere under neural stem cell culture conditions. Furthermore, H-rasV12-overexpressing p53−/− astrocytes (p53−/−ast-H-rasV12) possess an in vitro self-renewal capacity, and are aberrantly differentiated into Tuj1-positve neurons both in vitro and in vivo. Amongst a variety of Ras-mediated canonical signaling pathways, we demonstrated that the MEK/ERK signaling pathway is responsible for neurosphere formation in p53-deficient astrocytes, whereas the PI3K/AKT signaling pathway is involved in oncogenic transformation in these cells. These findings suggest that the activation of Ras signaling pathways promotes the generation of brain cancer stem-like cells from p53-deficient mouse astrocytes by changing cell fate and transforming cell properties. |
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Keywords: | Astrocyte Brain cancer stem-like cells Cell differentiation fate Glioma H-ras p53 |
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