Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Becaplermin
-
Brain / drug effects
-
Brain / physiology
-
Brain Neoplasms / genetics*
-
Brain Neoplasms / pathology
-
Cells, Cultured
-
Cyclin-Dependent Kinase Inhibitor p16 / genetics*
-
Diploidy
-
Enzyme Activation
-
Gene Deletion
-
Gene Transfer Techniques
-
Genes, p53 / physiology*
-
Glioblastoma / genetics*
-
Glioblastoma / pathology
-
Humans
-
Mice
-
Mice, Inbred C57BL
-
Platelet-Derived Growth Factor / pharmacology*
-
Protein Serine-Threonine Kinases*
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins c-akt
-
Proto-Oncogene Proteins c-sis / genetics*
-
Proto-Oncogene Proteins c-sis / metabolism
-
Receptors, Platelet-Derived Growth Factor / metabolism
-
Tumor Suppressor Protein p14ARF / genetics*
Substances
-
Cyclin-Dependent Kinase Inhibitor p16
-
Platelet-Derived Growth Factor
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-sis
-
Tumor Suppressor Protein p14ARF
-
Becaplermin
-
Receptors, Platelet-Derived Growth Factor
-
AKT1 protein, human
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt