Domenico Grieco
Domenico Grieco
e-mail:
affiliation: Università di Napoli Federico II
research area(s): Cell Biology, Cancer Biology
Course: Molecular Pathology and Pathophysiology
University/Istitution: Università di Napoli Federico II
Education
1985: MD degree, University of Naples Federico II, Italy
1992: PhD in Cellular and Molecular Biology and Pathology, University of Naples Federico II, Italy

Employment and research experience
1986-88: Fogarty Visiting Fellowship. Fogarty Fellow, NIDDK, NIH, Bethesda, USA at Dr. E. Rall Laboratory.
Hormonal regulation of the malic enzyme gene expression. Regulation of the cAMP-PKA pathway in normal and transformed cell lines.
1990-93: Fellowship from American Italian Foundation for Cancer Research. Postdoctoral Fellow, Institute of Cancer Research of Columbia University, New York, USA at Dr. M. E. Gottesman Laboratory.
Role for the cAMP-PKA pathway in the cell division cycle.
1993-95: Fellowships from American Italian Foundation for Cancer Research and from Italian Association for Cancer Research. Visiting Scientist, Institute of Cancer Research of Columbia University, New York, USA at Dr. M. E. Gottesman Laboratory.
Role for the cAMP-PKA pathway in the cell division cycle.
1995-96: Fellowship from Italian National Council of Research at Department of Cellular and Molecular Biology and Pathology, University of Naples Federico II, Italy.
1998-2002: Assistant Professor of General Pathology, Department of Experimental and Clinical Medicine, Medical School of the University of Catanzaro, Italy.
Mechanisms of DNA replication and of the DNA damage response. Mechanisms controlling the completion of mitosis.
2002-present: Associate Professor of General Pathology, Department of Cellular and Molecular Biology and Pathology, Faculty of Biotechnological Sciences, University of Naples Federico II, Italy.
Mechanisms controlling chromosome segregation. The action of the spindle assembly checkpoint. Mechanisms of the DNA damage response.

Awards
1998: Awarded by one out of 5 Grants from Italian Association for Cancer Research dedicated to establish new research units "New Unit Start Up Grant" (NUSUG) to the project entitled "Role for the cAMP-PKA pathway in the cell division cycle" for a five years period.

Editorial Positions
2004-to present: Faculty Member of the "Faculty of 1000 Biology" (Cell Growth and Division
Section)
2008-to present: Editorial Board Member of The Open Enzyme Inhibition Journal; Betham open publisher

Editorial Activities
Reviewer for Genes and Development, PLoS Biology, The Journal of Biological Chemistry, Developmental Biology, Oncogene

Invited Speaker
1995 4th Jacques Monod conference "The cell division cycle", Aussois, France "Maturation Promoting Factor-dependent activation of the cAMP-PKA pathway triggers the transition from mitosis to interphase in the Xenopus cell cycle.
1996 Gordon conference "Second messengers and protein phosphorylation", New Hampshire, USA "PKA and exit from mitosis"
1997 Molecular oncology meeting, Positano, Italy "Mitosis control in Xenopus"
2004 First IEO-IFOM meeting on cancer, Milano, Italy "Cdk1 at mitosis exit: a regulated regulator"
2006 SIBBM meeting "The cell cycle", Roma, Italy "Cdk1 activity at mitosis exit"
The group of Prof. Domenico Grieco studies the surveillance mechanisms called cell cycle checkpoints. Cell cycle checkpoints ensure genome stability during the cell division cycle by controlling that a cell cycle phase begins only when the previous has been successfully completed. A deeper understanding of such mechanisms is extremely relevant for human diseases, as checkpoint failure is cause of genomic instability, a hallmark of cancer cells.
One of the laboratory main project focuses on the study of the Spindle Assembly Checkpoint (SAC). SAC senses incomplete mitotic spindle assembly and inhibits the proteolysis-dependent pathway required for mitosis exit until correct spindle assembly completion. Thus, both SAC activation and its timely inactivation ensure accurate chromosome segregation in mitosis. We have recently found evidence that SAC silencing required a phosphatase to reverse SAC-sustaining phosphorylations (Visconti et al. Cell Cycle, 2010). We have now gathered preliminary data identifying the phosphatase and its relevant substrates involved in SAC silencing. Thus, in the following years, we will study in more details the molecular mechanisms regulating phosphatase activation at the end of mitosis. We believe that a further understanding of the SAC-regulating mechanisms safeguarding chromosomal stability will offer the opportunity for new diagnostic-prognostic as well as therapeutic approaches to cancer management.
Another laboratory main project project focuses on the study of the ATM gene, encoding for a large Ser/Thr protein kinase playing a key role in the DNA damage checkpoint. Mutations in the ATM gene cause Ataxia-Telangiectasia (A-T), an autosomal recessive disorder for which there is no specific cure at present. However, not all the A-T features can be explained solely by defects in the DNA damage response (DDR). To search for DDR-independent ATM functions, we analyzed the effects of chemical or genetic ATM downregulation in cells in the absence of DNA damaging insults and consistently found defects in mitotic spindle assembly. This observation may already explain some aspects of the A-T syndrome such as the premature aging phenotype, being the control of spindle positioning indeed crucial for regulating asymmetric cell division in stem cell niches. Thus, in the following years, we will focus on the identification of the molecular mechanisms by which ATM regulates spindle assembly. Remarkably, we expect the identification of novel ATM functions not only to contribute to the comprehension of the basic pathological mechanisms of the A-T syndrome but also to provide a new rationale for therapeutic intervention.
Cosentino C, Grieco D, Costanzo V (2011) ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair. EMBO J 30:564-55

Bocchino M, Agnese S, Fagone E, Svegliati S, Grieco D, Vancheri C, Gabrielli A, Sanduzzi A, Avvedimento EV (2010) Reactive oxygen species are required for maintenance and differentiation of primary lung fibroblasts in idiopathic pulmonary fibrosis. PLoS One 5:e14003

Visconti R, Palazzo L, Grieco D (2010) Requirement for proteolysis in spindle assembly checkpoint silencing. Cell Cycle 9:564-9
Visconti R, Grieco D (2009) New insights on oxidative stress in cancer. Curr Opin Drug Discov Devel. 12:240-5

D'Angiolella V, Santarpia C, Grieco D (2007) Oxidative stress overrides the spindle checkpoint. Cell Cycle 6:576-9

D'Angiolella V, Palazzo L, Santarpia C, Costanzo V, Grieco D (2007) Role for non-proteolytic control of M-phase-promoting factor activity at M-phase exit. PLoS One 2:e247
Project Title:
Identification of new mechanisms for spindle assembly checkpoint silencing.


Project Title:
Identification of new mechanisms of action of the Ataxia-Telangiectasia Mutated (Atm) gene product.