Stefano Campaner

Italian Institute of Technology (IIT), Genova, Liguria, Italy

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Publications (11)135.14 Total impact

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    ABSTRACT: The c-myc proto-oncogene product, Myc, is a transcription factor that binds thousands of genomic loci 1 . Recent work suggested that rather than up-and downregulating selected groups of genes 1–3 , Myc targets all active promoters and enhancers in the genome (a phenomenon termed 'invasion') and acts as a general amplifier of transcription 4,5 . However, the available data did not readily discrim-inate between direct and indirect effects of Myc on RNA biogenesis. We addressed this issue with genome-wide chromatin immunopre-cipitation and RNA expression profiles during B-cell lymphoma-genesis in mice, in cultured B cells and fibroblasts. Consistent with long-standing observations 6 , we detected general increases in total RNA or messenger RNA copies per cell (hereby termed 'amplification') 4,5 when comparing actively proliferating cells with control quiescent cells: this was true whether cells were stimulated by mitogens (requiring endogenous Myc for a proliferative response) 7,8 or by deregulated, oncogenic Myc activity. RNA amplification and promoter/enhancer invasion by Myc were separable phenomena that could occur without one another. Moreover, whether or not associated with RNA amp-lification, Myc drove the differential expression of distinct subsets of target genes. Hence, although having the potential to interact with all active or poised regulatory elements in the genome 4,5,9–11
    Nature 07/2014; DOI:10.1038/nature13537 · 42.35 Impact Factor
  • Sara Rohban, Stefano Campaner
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    ABSTRACT: Myc is a cellular oncogene frequently deregulated in cancer that has the ability to stimulate cellular growth by promoting a number of proliferative and pro-survival pathways. Here we will focus on how Myc controls a number of diverse cellular processes that converge to ensure processivity and robustness of DNA synthesis, thus preventing the inherent replicative stress responses usually evoked by oncogenic lesions. While these processes provide cancer cells with a long-term proliferative advantage, they also represent cancer liabilities that can be exploited to devise innovative therapeutic approaches to target Myc overexpressing tumors. This article is part of a Special Issue entitled: Myc proteins in cell biology and pathology, edited by Dr. Giovanni Perini and Dr. Barbara Majello.
    Biochimica et Biophysica Acta 04/2014; 1849(5). DOI:10.1016/j.bbagrm.2014.04.008 · 4.66 Impact Factor
  • Sara Rohban, Stefano Campaner
    Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 01/2014; · 5.44 Impact Factor
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    ABSTRACT: A precise balance between quiescence and proliferation is crucial for the lifelong function of hematopoietic stem cells (HSCs). Cyclins E1 and E2 regulate exit from quiescence in fibroblasts, but their role in HSCs remains unknown. Here, we report a non-redundant role for cyclin E1 in mouse HSCs. A long-term culture-initiating cell (LTC-IC) assay indicated that the loss of cyclin E1, but not E2, compromised the colony-forming activity of primitive hematopoietic progenitors. CcnE1(-/-) mice showed normal hematopoiesis in vivo under homeostatic conditions but a severe impairment following myeloablative stress induced by 5-fluorouracil (5-FU). Under these conditions, CcnE1(-/-) HSCs were less efficient in entering the cell cycle, resulting in decreased hematopoiesis and reduced survival of mutant mice upon weekly 5-FU treatment. The role of cyclin E1 in homeostatic conditions became apparent in aged mice, where HSC quiescence was increased in CcnE1(-/-) animals. On the other hand, loss of cyclin E1 provided HSCs with a competitive advantage in bone marrow serial transplantation assays, suggesting that a partial impairment of cell cycle entry may exert a protective role by preventing premature depletion of the HSC compartment. Our data support a role for cyclin E1 in controlling the exit from quiescence in HSCs. This activity, depending on the physiological context, can either jeopardize or protect the maintenance of hematopoiesis.
    Cell cycle (Georgetown, Tex.) 09/2013; 12(23). DOI:10.4161/cc.26584 · 5.01 Impact Factor
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    Stefano Campaner, Bruno Amati
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    ABSTRACT: Activation of oncogenes is generally associated with the induction of DNA damage response (DDR) signaling, which acts as a barrier to tumor progression. In this review we will present an overview of the DDR associated with oncogenic activation of Myc, with special focus on two opposite and paradoxical aspects of this response: (1) the role of the Myc-induced DDR in tumor suppression; (2) its role in dampening Myc-induced replication stress, thereby protecting the viability of prospective cancer cells. These opposing effects on cancer progression are controlled by two different branches of DDR signaling, respectively ATM/CHK2 and ATR/CHK1. Indeed, while ATM activity constitutes a barrier to malignant transformation, full activation of ATR and CHK1 is essential for tumor maintenance, providing important opportunities for therapeutic intervention. Thus, the Myc-induced DDR acts as a double-edged sword in tumor progression.
    Cell Division 02/2012; 7(1):6. DOI:10.1186/1747-1028-7-6 · 2.63 Impact Factor
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    ABSTRACT: Oncogene-induced replicative stress activates an Atr- and Chk1-dependent response, which has been proposed to be widespread in tumors. We explored whether the presence of replicative stress could be exploited for the selective elimination of cancer cells. To this end, we evaluated the impact of targeting the replicative stress-response on cancer development. In mice (Mus musculus), the reduced levels of Atr found on a mouse model of the Atr-Seckel syndrome completely prevented the development of Myc-induced lymphomas or pancreatic tumors, both of which showed abundant levels of replicative stress. Moreover, Chk1 inhibitors were highly effective in killing Myc-driven lymphomas. By contrast, pancreatic adenocarcinomas initiated by K-Ras(G12V) showed no detectable evidence of replicative stress and were nonresponsive to this therapy. Besides its impact on cancer, Myc overexpression aggravated the phenotypes of Atr-Seckel mice, revealing that oncogenes can modulate the severity of replicative stress-associated diseases.
    Nature Structural & Molecular Biology 11/2011; 18(12):1331-5. DOI:10.1038/nsmb.2189 · 11.63 Impact Factor
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    ABSTRACT: p53 is the central regulator of cell fate following genotoxic stress and oncogene activation. Its activity is controlled by several posttranslational modifications. Originally defined as a critical layer of p53 regulation in human cell lines, p53 lysine methylation by Set7/9 (also called Setd7) was proposed to fulfill a similar function in vivo in the mouse, promoting p53 acetylation, stabilization, and activation upon DNA damage (Kurash et al., 2008). We tested the physiological relevance of this circuit in an independent Set7/9 knockout mouse strain. Deletion of Set7/9 had no effect on p53-dependent cell-cycle arrest or apoptosis following sublethal or lethal DNA damage induced by radiation or genotoxic agents. Set7/9 was also dispensable for p53 acetylation following irradiation. c-myc oncogene-induced apoptosis was also independent of Set7/9, and analysis of p53 target genes showed that Set7/9 is not required for the p53-dependent gene expression program. Our data indicate that Set7/9 is dispensable for p53 function in the mouse.
    Molecular cell 08/2011; 43(4):681-8. DOI:10.1016/j.molcel.2011.08.007 · 14.46 Impact Factor
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    ABSTRACT: Eukaryotic Initiation Factor 6 (eIF6) controls translation by regulating 80S subunit formation. eIF6 is overexpressed in tumors. Here, we demonstrate that eIF6 inactivation delays tumorigenesis and reduces tumor growth in vivo. eIF6(+/-) mice resist to Myc-induced lymphomagenesis and have prolonged tumor-free survival and reduced tumor growth. eIF6(+/-) mice are also protected by p53 loss. Myc-driven lymphomas contain PKCβII and phosphorylated eIF6; eIF6 is phosphorylated by tumor-derived PKCβII, but not by the eIF4F activator mTORC1. Mutation of PKCβII phosphosite of eIF6 reduces tumor growth. Thus, eIF6 is a rate-limiting controller of initiation of translation, able to affect tumorigenesis and tumor growth. Modulation of eIF6 activity, independent from eIF4F complex, may lead to a therapeutical avenue in tumor therapy.
    Cancer cell 06/2011; 19(6):765-75. DOI:10.1016/j.ccr.2011.04.018 · 23.89 Impact Factor
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    ABSTRACT: The aberrant activation of oncogenic pathways promotes tumor progression, but concomitantly elicits compensatory tumor-suppressive responses, such as apoptosis or senescence. For example, Ras induces senescence, while Myc generally triggers apoptosis. Myc is in fact viewed as an anti-senescence oncogene, as it is a potent inducer of cell proliferation and immortalization, bypasses growth-inhibitory signals, and cooperates with Ras in cellular transformation. Recent reports prompt re-evaluation of Myc-induced senescence and of its role in tumor progression and therapy. We have shown that the cyclin-dependent kinase Cdk2, although redundant for cell cycle progression, has a unique role in suppressing a Myc-induced senescence program: Myc activation elicited expression of p16(INK4a) and p21(Cip1), and caused senescence in cells lacking Cdk2, but not in Cdk2-proficient cells. We show here that suppression of Myc-induced senescence by Cdk2 does not occur through phosphorylation of its purported substrate residue in Myc (Ser 62). Additional cellular activities have been identified that suppress Myc-induced senescence, including the Wrn helicase, Telomerase and Miz1. These senescencesuppressing activities were critical for tumor progression, as deficiency in either Cdk2, telomerase or Miz1 reduced the onset of Myc-induced lymphoma in transgenic mice. Other gene products like p53, SUV39H1 or TGFβ promoted senescence, which together with apoptosis contributed to tumor suppression. Paradoxically, Myc directly counteracted the very same senescence program that it potentially elicited, since it positively regulated Wrn, Telomerase and Cdk2 activity. Furthermore, Cdk2 inhibition re-activated the latent senescence program in Myc expressing cells. Hence, while these molecules are instrumental to the oncogenic action of Myc, they may simultaneously constitute its Achille's heel for therapeutic development.
    Cell cycle (Georgetown, Tex.) 09/2010; 9(18):3655-61. DOI:10.4161/cc.9.18.13049 · 5.01 Impact Factor
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    ABSTRACT: Activated oncogenes induce compensatory tumour-suppressive responses, such as cellular senescence or apoptosis, but the signals determining the main outcome remain to be fully understood. Here, we uncover a role for Cdk2 (cyclin-dependent kinase 2) in suppressing Myc-induced senescence. Short-term activation of Myc promoted cell-cycle progression in either wild-type or Cdk2 knockout mouse embryo fibroblasts (MEFs). In the knockout MEFs, however, the initial hyper-proliferative response was followed by cellular senescence. Loss of Cdk2 also caused sensitization to Myc-induced senescence in pancreatic beta-cells or splenic B-cells in vivo, correlating with delayed lymphoma onset in the latter. Cdk2-/- MEFs also senesced upon ectopic Wnt signalling or, without an oncogene, upon oxygen-induced culture shock. Myc also causes senescence in cells lacking the DNA repair protein Wrn. However, unlike loss of Wrn, loss of Cdk2 did not enhance Myc-induced replication stress, implying that these proteins suppress senescence through different routes. In MEFs, Myc-induced senescence was genetically dependent on the ARF-p53-p21Cip1 and p16INK4a-pRb pathways, p21Cip1 and p16INK4a being selectively induced in Cdk2-/- cells. Thus, although redundant for cell-cycle progression and development, Cdk2 has a unique role in suppressing oncogene- and/or stress-induced senescence. Pharmacological inhibition of Cdk2 induced Myc-dependent senescence in various cell types, including a p53-null human cancer cell line. Our data warrant re-assessment of Cdk2 as a therapeutic target in Myc- or Wnt-driven tumours.
    Nature Cell Biology 12/2009; 12(1):54-9; sup pp 1-14. DOI:10.1038/ncb2004 · 20.06 Impact Factor

Publication Stats

267 Citations
135.14 Total Impact Points

Institutions

  • 2012–2014
    • Italian Institute of Technology (IIT)
      Genova, Liguria, Italy
  • 2013
    • IIT Research Institute (IITRI)
      Chicago, Illinois, United States
  • 2009–2011
    • IEO - Istituto Europeo di Oncologia
      • Department of Experimental Oncology
      Milano, Lombardy, Italy