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Oncogenes, Chromatin and Cell Cycle Control

bruno amati

[IEO] and [IIT]
Coordinator, Center for Genomic Science of IIT@SEMM,
Italian Institute of Technology

Bruno Amati, PhD
c/o IFOM-IEO Campus, Via Adamello, 16 - 20139 Milan, Italy
Tel. +39 02 57489824 - Fax. +39 02 94375990

Research project

fig 1fig.1, Myc is an intracellular sensor and transducer of extracellular stimuli [+ zoom]

Oncogenic signals induce cell cycle progression and malignant transformation, but concomitantly elicit tumor-suppressive mechanisms (including apoptosis, senescence, and/or DNA Damage Responses), which must be bypassed in order to allow tumor progression, and which constitute the main selective pressure for mutation and/or silencing of tumor suppressor genes. Apoptosis and senescence also determine the 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.

fig 2fig.2, The Myc - Max - Mad Network [+ zoom]

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 transcription (fig. 3).

fig 1fig.3, Myc functions as an activator or repressor of different target genes [+ zoom]

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 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 immunoprecipitation (qChIP) protocols, previously developed and optimized in our group, with high-throughput genome analysis tools available at the IFOM-IEO Campus.

update: March 2007
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