Oncogenes, Chromatin and Cell Cycle Control by steepslope9876


									       Oncogenes, Chromatin and Cell Cycle Control

       Bruno AMATI, Ph.D.

STAFF Post-doctoral Fellows: Stefano Campaner, Ph.D.,                 Activities 2007. Oncogenic signals induce
      Chiara Gorrini, Ph.D., Ernesto Guccione, Ph.D.,                 cell cycle progression and malignant transformation,
      Arianna Sabò, Ph.D., Victor Sanchez-Arevalo, Ph.D.,             but concomitantly elicit tumor-suppressive mechanisms
      Thomas Schleker, Ph.D, Alison Patricia Smith, Ph.D.             (including apoptosis, senescence, and/or DNA Damage
      Students: Samantha Bennett, Giovanni Faga’, Daniele Gaudiosi,   Responses), which must be bypassed in order to allow
      Francesca Martinato, Daniele Perna, Mariaelena Pistoni          tumor progression, and which constitute the main selective
      Technicians: Mirko Doni, Alessandro Verrecchia                  pressure for mutation and/or silencing of tumor suppressor
      Undergraduate Students: Lucia Bianchi, Fabio Casadio,           genes. Apoptosis and senescence also determine the
      Serena De Fazio                                                 therapeutic efficacy of genotoxic treatments (whether
                                                                      chemo- or radio-therapy). Hence, the same genetic
                                                                      lesions and/or epigenetic alterations that allow tumor
                                                                      progression also influence therapeutic responses.

                                                                      Our group has a long-standing interest in the c-myc
                                                                      oncogene and its product, the Myc protein. Under
                                                                      physiological circumstances, Myc is a central regulator
                                                                      of the cellular responses to extracellular stimuli. When
                                                                      its activities become uncontrolled, however, Myc acquires
                                                                      potent oncogenic properties (fig. 1). Myc is a transcription
                                                                      factor: it functions as a heterodimer with a unique partner,
                                                                      Max, which itself forms alternative complexes with
                                                                      factors that can antagonize Myc function (fig. 2). The
                                                                      Myc/Max dimer directly or indirectly binds a multitude
                                                                      of target genes, and can either activate or repress tran-
                                                                      scription (fig. 3).

                                                                      In general terms, our research aims at explaining the
                                                                      oncogenic activity of Myc, the tumor suppressor pathways
                                                                      that antagonize it, and their impact on tumorigenesis. In
                                                                      order to dissect the pathways involved in those biological
                                                                      responses, we rely on a combination of molecular
                                                                      genetics, cell biology and mouse tumor models. We are
                                                                      focusing in particular on the roles of cell cycle regulators
                                                                      (cyclins, cyclin-dependent kinases and their inhibitors),
                                                                      chromatin-modifying enzymes (e.g. histone acetyl- and
                                                                      methyl-transferases) and Myc-target genes.

                                                                      We also use Myc as a paradigm to study the epigenetic
                                                                      organization and regulation of the genome. In particular,
                                                                      we are interested in understanding how specific chromatin

       IEO — Scientific Report 2007 — Ongoing research 2008
environments - or epigenetic states - determine recognition
of transcription factor-binding sites in the human and
mouse genomes, and how the same transcription factors
further modify chromatin to regulate gene expression.
These studies combine quantitative chromatin immuno-
precipitation (qChIP) protocols, previously developed and
optimized in our group, with high-throughput genome
analysis tools available at the IFOM-IEO Campus.

                                                              IEO — Scientific Report 2007 — Ongoing research 2008

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