Upsala Journal of Medical Sciences. 2012; 117: 122–131 REVIEW ARTICLE Myc proteins in brain tumor development and maintenance FREDRIK J. SWARTLING Uppsala University, Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden Abstract Myc proteins are often deregulated in human brain tumors, especially in embryonal tumors that affect children. Many observations have shown how alterations of these pleiotropic Myc transcription factors provide initiation, maintenance, or progression of tumors. This review will focus on the role of Myc family members (particularly c-myc and Mycn) in tumors like medulloblastoma and glioma and will further discuss how to target stabilization of these proteins for future brain tumor therapies. Key words: Brain tumors, molecular biology, oncogenes, pediatrics, protein phosphorylation, tumor biology Introduction The Myc family comprises the transcription factors c-myc, Mycn, and Mycl (1). Myc proteins are impor- tant for normal development, especially c-myc and Mycn which are embryonically lethal when knocked out (2-4) in transgenic mice. Transgenic mice present a severely diminished forebrain and hindbrain when Mycn is speciﬁcally abrogated in nestin-positive neural stem and precursor cells (NSCs) of the deve- loping brain (5), while a similar conditional c-myc knock-out moderately impairs brain growth (6). Nestin-driven transgenes for double c-myc and Mycn depletion have a nervous system phenotype that is much more severe than either Myc gene knock-out alone (7,8). These ﬁndings collectively suggest that Myc proteins are essential for brain development. Overexpression of c-myc in nestin-pos- itive NSCs promotes cell proliferation (9), and many human tumors including brain tumors express high levels of or show gene ampliﬁcations of Myc family members. This is true for medulloblastoma (10–12) and glioma (13–15), the most common malignant types of brain tumors in children and adults, respec- tively. It is also true for other brain tumor types, like primitive neuroectodermal tumors (PNETs) (16). Similarly, overexpressed c-myc or Mycn have been found to initiate different types of brain tumors like medulloblastoma (17–20), PNETs (21), and glioma (22,23) in mice. In most of these cases Myc genes generate tumors after a rather long latency or in combination with other oncogenes (like Ras, Akt, Shh, or beta-catenin) or tumor suppressor genes (e.g. p53, Ptc, Ink4c). This suggests a necessary involvement of one or more additional transforming events before a full-blown cancer can develop. It is not known in detail how Myc proteins use other cancer genes to induce these tumors and if there is a diffe- rence in how the different Myc proteins are involved in brain tumor initiation. This is also difﬁcult to study as Myc genes target a large number of other genes and regulate important cellular mechanisms like prolife- ration, apoptosis, DNA repair, metabolism, ribosome biogenesis, and protein synthesis (24). Clearly, Myc Correspondence: Fredrik J. Swartling, Uppsala University, Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden. E-mail: fredrik.swartling@igp.uu.se (Received 7 October 2011; accepted 16 January 2012) ISSN 0300-9734 print/ISSN 2000-1967 online 2012 Informa Healthcare DOI: 10.3109/03009734.2012.658975