- Role: Ricercatore
- Office:U3 stanza 5013-5011
- Telephone number:02- 64483521-13
- Reception Hours:martedì dalle 14 alle 15
- Corso di Laurea in Biotecnologie -LTA Biochimiche
- Corso di Laurea in Biotecnologie – Biochimica cellulare
- Mitotic spindle mis-orientation in carcinogenesis: from yeast model to colorectal cancer, in collaboration with Dr. Paola Fusi (BtBs) and Simonetta Piatti (Montpellier, France).
- Transcriptomic, proteomic and metabolomics approaches to unveil hidden key molecular determinants of cellular proliferation in eukaryotic systems.
- Yeast as a model to investigate the molecular mechanism of metabolic disorders.
SNF1/AMPK IN EUKARYOTIC SYSTEMS: SEVERAL FUNCTIONS IN ONE KINASE
Yeast as a model to investigate the molecular mechanism of metabolic disorders
In the last years Dr. Coccetti’s laboratory carried out several projects in the field of cell cycle regulation using S. cerevisiae as a model. The regulation of the G1/S transition, with particular regard to the main key proteins involved in such a regulation (Cdk1, the principal cyclin-dependent kinase; Sic1, the principal Cdk1 inhibitor; Cdc34, the ubiquitin conjugating enzyme and the essential and ubiquitous protein kinase CK2) were deeply investigated.
Actually, the research is focused on the role of the energy sensor Snf1/AMPK in controlling cell growth, proliferation and metabolism both in yeast and mammalian cells. The S. cerevisiae orthologue of AMPK, Snf1, shares evolutionary conserved features with its counterparts in other eukaryotes and is essential in yeast for the growth in the presence of low glucose concentration and in the utilization of alternative carbon sources. Moreover, we have recently showed that Snf1 is a key metabolic regulator also in non-limiting glucose conditions, supporting the usefulness of yeast as a model organism for the study of the metabolism of proliferating eukaryotic cells with alterations in the AMPK signalling network.
Loss of Snf1/AMPK activity determines a reliance on amino acid utilization for growth in yeast, a typical hallmark of cancer cells. Using an integrative biology approach (transcriptomics, metabolomics and proteomics of post-translational modifications analysis), the primary aims of the present project are: (i) to deeply characterize the role of Snf1/AMPK activity in the regulation of metabolism and gene expression as a function of glucose and amino acid concentrations; (ii) to investigate the role of Snf1/AMPK in bioenergetics; (iii) to examine the connection among AMPK and the main signal transduction networks in yeast as well as in models of human cancer cell lines, also by using specific chemical modulators of AMPK activity. Qualitative and quantitative results from the different analytical levels are computationally integrated and contextualized in the frame of the existing knowledge to better elucidate the molecular mechanisms involved in metabolic dysfunctional diseases.
Novel AMPK activators as promising small molecules for in vivo treatment of colorectal cancer.
New drugs with anti-proliferative activity on colorectal cancer (CRC) are now under study in P. Coccetti’s laboratory. A series of novel 1,4-diaryl-2-azetidinones synthesized by Dr. R. Pagliarin (University of Milano) were evaluated for G2/M cell cycle arrest and inhibition of tubulin polymerization against several CRC cell lines. This effect was accompanied by activation of AMPK and caspase-3, as well as induction of apoptosis. Additionally, the most active compound displayed a significant anti-tumour growth delay in a mouse xenograft model of colorectal cancer. Taking advantage of the mass-spectrometry facilities in the laboratory of Prof. G. Tedeschi (University of Milano), we are now involved in identifying the candidate targets of this compound in order elucidate its molecular mechanism and to open the route to a new class of potential therapeutic agents.
Paola Coccetti – Head of lab – Assistant Professor
office 5011/5013, V floor, building U3
tel. +39 02 6448 3521/3513
see also: PubMed, BOA, Google scholar, ORCID, Scopus, #BtBsPub
Budding yeast S. cerevisiae is widely used as a model due to its ease of manipulation and rapid growth compared to animal model. In addition, the maturity of yeast’s biochemistry, cell biology and genetic has positioned it as the primary platform for development of many high-throughput technologies, including transcriptome, proteome and metabolome screens.
We are actually using yeast to understand the interplay among metabolism, proliferation and AMPK signalling, the master regulator of energy homeostasis in eukaryotic cells. Our scientific interests are focused on understanding the key molecular mechanisms of these networks as well as their potential in therapeutics.
Farida Tripodi – PostDoc
room 5011, V floor , building U3
tel: +39 02 6448 3513
see also: PubMed, BOA
Prof.ssa Gabriella Tedeschi, Università degli Studi di Milano
Dr. Roberto Pagliarin, Università degli Studi di Milano
Dr. Riccardo Rossi, INGM, Milano
Prof. Gennaro Agrimi, Università di Bari
Prof. Leah E. Cowen, University of Toronto, Toronto, Canada