Nuclear Receptor Research

Transcription Factors Synergistically Activated at the Crossing of the Restriction Point between G1 and S Cell Cycle Phases. Pathologic Gate Opening during Multi-Hit Malignant Transformation

Author(s): Nicoletta Castagnino, Massimo Maffei, Lorenzo Tortolina, Gabriele Zoppoli, Daniela Piras, Alessio Nencioni, Alberto Ballestrero, Franco Patrone, and Silvio Parodi

Transcription factors (TFs) represent key regulators of gene-expression patterns controlling cell behavior. TFs are active at nuclear – chromatin levels. TFs do not act in isolation; small sets of TFs cooperate toward the transcription of sets of mRNAs and consequently the translation of new proteins (the molecular phenotypes of a cell). Most TFs are activated through a cascade of biochemical reactions mediated by receptors expressed on the target cell surface. Nuclear Receptors (NRs) are transcription factors activated instead by small hydrophobic molecules capable of crossing the plasma membrane. The convergence of different pathways on TFs and their posttranslational modifications ensure that the external stimuli generate appropriate and integrated responses. The reconstruction of the molecular anatomy of these pathways through Molecular Interactions Maps (MIMs) can depict these intricate interactions. A mathematical modeling approach simulates/mimics their mechanism of action in normal and pathological conditions. We can simulate the effect of virtual hits in neoplastic transformation as mutations/alterations in these pathways. We can also simulate the effect of targeted inhibitors on these deregulated pathways. This strategy can help to guide an appropriate combination of targeted drugs in the treatment of a cancer patient, a major innovative perspective of incoming years.