Complementary effects of platelet-derived growth factor autocrine stimulation and p53 or Ink4a-Arf deletion in a mouse glioma model.
INK4a-ARF and p53 inactivation are common but rarely concurrent findings in glioblastoma multiforme. Here we demonstrate that experimental deletion of either tumor suppressor gene cooperates with retrovirally expressed platelet-derived growth factor (PDGF)-B regarding both tumor latency and frequency in a mouse brain tumor model. We find indications of PTEN down-regulation and increased Akt phosphorylation in both types of null tumors (although more prominent in p53-/- tumors) suggesting a possible mechanism for this synergism. This is the first time that the cooperative tumorigenic effects of PDGF-B stimulation and p53 loss of function are demonstrated in an in vivo model, establishing a functional link between two common molecular changes of human secondary glioblastoma multiforme.
Hesselager
Göran
G
Department of Genetics and Pathology, Rudbeck Laboratory, University Hospital, SE-75185 Uppsala, Sweden. goran.hesselager@genpat.uu.se
Uhrbom
Lene
L
Westermark
Bengt
B
Nistér
Monica
M
D000818:Animals; D000077214:Becaplermin; D001921:Brain / Q000187:drug effects / Q000502:physiology; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004171:Diploidy; D004789:Enzyme Activation; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D016158:Genes, p53 / Q000502:physiology*; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics* / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D025803:Tumor Suppressor Protein p14ARF; D000077214:Becaplermin; D017479:Receptors, Platelet-Derived Growth Factor; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt