Widening the concept of oncogene

As genomic cancer data bases and experimental studies progress, some genes reveal unsuspected roles in oncogenesis. We provide here a short survey on some key examples to illustrate the need to reconsider our current definition of oncogene. As age advances, somatic mutations in metabolic, signaling or regulation of apoptosis may trigger tumorigenesis, in particular if affecting damaged or precancerous cells. Decreasing mitochondrial respiration enhances glycolysis triggering the “Warburg effect”. The Isocitrate dehydrogenase (IDH1) converts isocitrate to 2oxoglutarate. Somatic mutations in cytoplasmic IDH1 and mitochondrial IDH2 are common early drivers in glioma and acute myeloid leukaemia (AML) [1], being most frequent in diffuse gliomas and secondary glioblastoma [2]. In a similar context, mitochondrial respiratory chain complexes (RC) catalyze a cascade of oxidation reactions to generate ATP. Mutations in RC complexes I and II are frequent in cancer cells, where they contribute to form reactive oxygen species which result fatal for the cell. In addition, mutations in RC components prevent the apoptosis of tumoral cells and represent bad prognosis markers in cancer [3]. Kinases activation can be the primary event during oncogenesis or a secondary event as recipient of oncogenic signaling. Tyrosine kinases (EGFR, PDGFR or Src) and serine-threonine kinases (Raf or Akt) are well characterized and lead to cell proliferation and inhibition of apoptosis. However, among the family of kinases directly involved in cancer, some are not yet considered canonical oncogenes. For example, the apoptosis signal-regulating kinase 1 (ASK1), a MAP kinase-kinase-kinase implicated in apoptosis, inflammation, proliferation and migration, activates cJun N-terminal kinase (JNK) and p38 and is clearly related to tumorigenesis in liver, skin, melanoma and colon cancers [4] . While these metabolic and signaling proteins could easily be accepted as new members of the oncogene class, others are unsuspected arrivals. During recent years some muscular proteins have been related to cell proliferation and oncogenic transformation. The myocyte enhancer transcription factor 2 (Mef2) synergizes with Notch to stimulate proliferation and metastasis [5]. The Troponin-Tropomyosin complex regulates muscle contraction through the acto-myosin Editorial