124 F. J. Swartling Growth stimulatory signals from Myc-collaborating oncogenes PI3K/Akt GSK3β Axin 1 PIN 1 PP2A P P 8 S62 T5 Myc e.g., ERK or Cdk1 mTORC1 T58 P S62 Myc Ub Ub Ub Ub Proteasomal degradation Usp28 Fbw7 P 8 S62 T5 Myc P T58 S62 Myc Replacement by e.g., Mad, Mnt In 26S proteasome for destruction Dimers formed with other bHLHs e.g., Max, Miz-1 Myc Partner bHLH Gene regulation E-box DNA Figure 1. Schematic model of the regulatory pathways for Myc proteins from activating signals of collaborating oncogenes to protein destabilization and proteasomal degradation. Suggested activating pathways (in red) and inhibiting pathways (in green) with putative involvement in brain tumor development and maintenance. Myc signaling in normal brain Myc proteins are members of a large family of basic helix-loop-helix (bHLH) transcription factors. These protein members can form homo- or heterodimeric complexes with themselves or with other members of this family. One important prerequisite for Myc activ- ity is its interaction with a dimerization partner, the bHLH protein Max (Figure 1) (61). Such generated Myc-Max complexes bind to E-box sequences which are found in promoters of many genes that act to promote transcription and cell proliferation (62,63). Through Miz1-complexes Myc and Max have been shown to have repressive functions (64) inhibiting tumor suppressor genes/cell cycle regulators like p15Ink4b and also p21Cip1 (65), where Myc represses p21Cip1 expression via a Miz1-dependent interaction with the p21 promoter (66). Moreover, the partners Mad or Mnt (another bHLH protein) act in Max-dimeric complexes transcriptionally to repress genes associated with E-box sequences (67). Myc members are differently expressed in normal brain. Mycl has no reported phenotype in knock- out mice but has particularly high expression in the ventricular zone of the embryonic midbrain (8,68). Mycn is highly expressed in developing forebrain and