title: Cdk2: a key regulator of the senescence control function of Myc.
abstract: Proto-oncogenes such as MYC and RAS promote normal cell growth but fuel tumor development when deregulated. However, over-activated Myc and Ras also trigger intrinsic tumor suppressor mechanisms leading to apoptosis and senescence, respectively. When expressed together MYC and RAS are sufficient for oncogenic transformation of primary rodent cells, but the basis for their cooperativity has remained unresolved. While Ras is known to suppress Myc-induced apoptosis, we recently discovered that Myc is able to repress Ras-induced senescence. Myc and Ras thereby together enable evasion of two main barriers of tumorigenesis. The ability of Myc to suppress senescence was dependent on phosphorylation of Myc at Ser 62 by cyclin-dependent kinase 2 (Cdk2), uncovering a new non-redundant role of this kinase. Further, utilizing Cdk2 as a cofactor, Myc directly controlled key genes involved in senescence. We speculate that this new role of Myc/Cdk2 in senescence has relevance for other Myc functions, such as regulation of stemness, self-renewal, immortalization and differentiation, which may have an impact on tissue regeneration. Importantly, selective pharmacological inhibition of Cdk2 forced Myc/Ras expressing cells into cellular senescence, highlighting this kinase as a potential therapeutic target for treatment of tumors driven by Myc or Ras.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hydbring
authors.forename: Lars-Gunnar
authors.initials: LG
authors.lastname: Larsson
mesh_terms: D000818:Animals; D017209:Apoptosis; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence / Q000502:physiology*; D051357:Cyclin-Dependent Kinase 2 / Q000502:physiology*; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D051357:Cyclin-Dependent Kinase 2; D018631:ras Proteins
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