Cell type-specific tumor suppression by Ink4a and Arf in Kras-induced mouse gliomagenesis.
Homozygous deletion of the INK4a-ARF locus is one of the most frequent mutations found in human glioblastoma. We have previously shown that combined Ink4a-Arf loss can increase tumor incidence in both glial progenitor cells and astrocytes during mouse gliomagenesis. Here we have investigated the separate contribution of loss of each of the tumor suppressor genes in glial progenitor cells and astrocytes in Akt + Kras-induced gliomagenesis. We show that Arf is the major tumor suppressor gene in both cell types. Arf loss generated glioblastomas from both nestin-expressing glial progenitor cells and glial fibrillary acidic protein-expressing astrocytes, with a significantly higher incidence in astrocytes. Ink4a loss, on the other hand, could only significantly contribute to gliomagenesis from glial progenitor cells and the induced tumors were of lower malignancy than those seen in Arf-deficient mice. Thus, Ink4a and Arf have independent and differential tumor suppressor functions in vivo in the glial cell compartment.
Uhrbom
Lene
L
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden. lene.uhrbom@genpat.uu.se
Kastemar
Marianne
M
Johansson
Fredrik K
FK
Westermark
Bengt
B
Holland
Eric C
EC
D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D011905:Genes, ras / Q000502:physiology*; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000166:cytology / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency / Q000235:genetics*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF