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Complementary Effects of Platelet-derived Growth Factor Autocrine Stimulation and p53 or Ink4a-Arf Deletion in a Mouse Glioma Model¹

Department of Genetics and Pathology, Rudbeck Laboratory, University Hospital, SE-75185 Uppsala, Sweden [G. H., L. U., B. W., M. N.]; Department of Neurosciences (Neurosurgery), University Hospital, SE-75185 Uppsala, Sweden [G. H.]; and Department of Oncology and Pathology, Karolinska Institutet, Karolinska Hospital, SE-17176 Stockholm, Sweden [M. N.]

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.

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