Brain cancer stem-like cell genesis from p53-deficient mouse astrocytes by oncogenic Ras.
Here, we show that H-ras(V12) causes the p53-knockout mouse astrocytes (p53-/- astrocytes) to be transformed into brain cancer stem-like cells. H-ras(V12) triggers the p53-/- astrocytes to express a Nestin and a Cd133, which are expressed in normal and cancer neural stem cells. H-ras(V12) also induces the formation of a single cell-derived neurosphere under neural stem cell culture conditions. Furthermore, H-ras(V12)-overexpressing p53-/- astrocytes (p53-/-ast-H-ras(V12)) 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.
Lee
Joong-Seob
JS
Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Anam-dong, Seongbuk-gu, Seoul 136-713, Republic of Korea.
Gil
Jung-Eun
JE
Kim
Jong-Hoon
JH
Kim
Tae-Kyung
TK
Jin
Xun
X
Oh
Se-Yeong
SY
Sohn
Young-Woo
YW
Jeon
Hye-Min
HM
Park
Hyo-Jung
HJ
Park
Jong-Whi
JW
Shin
Yong-Jae
YJ
Chung
Yong Gu
YG
Lee
Jang-Bo
JB
You
Seungkwon
S
Kim
Hyunggee
H
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D015415:Biomarkers / Q000032:analysis; D001932:Brain Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000032:analysis / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000737:chemistry / Q000473:pathology; D015689:Oncogene Protein p21(ras) / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014404:Tubulin / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D015415:Biomarkers; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; C462941:beta3 tubulin, mouse; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D015689:Oncogene Protein p21(ras)