EDUCATION/TRAINING

-University of Genoa, Genoa, Italy, B.Sc. (Bachelor of Sciences, 1987-1991
-University of Pavia, Pavia, Italy,M.Sc. (Master of Sciences),1992-1995
-University of Genoa, Genoa, Italy, Ph.D., 2000-2004

Positions and Employment:

March 2011- Associate professor of Genetics, University of Trento, Italy.
2010 – 2011 Assistant Professor –tenure track- in Genetics, University of Trento, Italy; PI, Laboratory of Transcriptional Networks, Centre for Integrative Biology, CIBIO, Trento, Italy
2005 – 2010 Assistant Researcher, Unit of Molecular Mutagenesis and DNA repair, National Cancer Research Institute, IST, Genoa Italy
2003 – 2004 Research Fellow, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIEHS, RTP, NC, USA
1999 – 2003 Visiting Fellow, Laboratory of Molecular Genetics, NIEHS, RTP, NC, USA
1997 – 1999 Guest Researcher, (American Italian Cancer Foundation Fellowship), Laboratory of Molecular Genetics, NIEHS, RTP, NC, USA
1994 – 1997 Research Fellow, Laboratory of Mutagenesis, National. Institute for Cancer Research (IST), Genoa, Italy

Other Experience and Professional Memberships:

2007-2008 Teaching appointment as Professor of Genetics, University of Genoa, Italy
2004- Member American Association for Cancer Research
2002-2003 Chief Judge, Transcription section, Fellowship Award for Research Excellence, NIH.
1995- Member Italian Society of Environmental Mutagenesis Honors
2000 & 2001 Fellowship award for Research Excellence (FARE)
1999 Young Researcher Award, Italian Society of Environmental Mutagenesis
1997 American Italian Cancer Foundation Fellowship

Our group focuses on the analysis of transcriptional network of stress responses, with an emphasis on sequence-specific transcription factors (TFs) that are involved in tumorigenesis. In particular, we are addressing the role of response element (RE) sequences in modulating transactivation specificity and the functional consequences of disease-associated mutations in transcription and of single nucleotide polymorphisms (SNPs) in RE sequences.

Research directions
Our group uses assay systems based in the eukaryotic model organism S. cerevisiae, which we refer to as an “in vivo test-tube”, as well as human cell lines. Specific projects are:

* Transcriptional cooperation between the tumor suppressor p53 and the estrogen receptors. The study draws upon our recent identification of a SNP in the Flt1 promoter. We have established that the Flt1 gene can be the target of cooperative interaction between stress-activated p53 and ligand-bound ER, mediated by two sub-optimal REs, one of which contains a SNP. These results depict a novel level of functional interactions among ERs and p53 and establish that both proteins can act as sequence-specific TFs at non-canonical REs. This type of transcriptional regulation sets an important example where environmentally distinct agents (e.g., ER ligands and radiation) could create a synergistic response at a common target gene.
* CDKN2A/p16INK4a 5'UTR variants in melanoma predisposition: lost in translation, somewhere.The CDKN2A gene is the most common high penetrance susceptibility gene identified to date in melanoma families. Rare polymorphisms or sequence variants at the CDKN2A/ p16INK4a 5'UTR, encountered during routine screening, are usually defined as variants with unknown significance after determining their frequency in control population and the cosegregation analysis in the family, when possible. We recently developed Monocistronic as well as bicistronic luciferase reporter vectors to study a panel of p16INK4a 5'UTR variants identified as heterozygous changes in patients from a hospital-based series of melanoma cases (c.-21C>T; c.-25C>T&c.-180G>A; c.-56G>T; c.-67G>C). We also applied polysomal profiling to measure allelic imbalance in heterozygous, patient-derived cell lines. The c.-21C>T variant but also c.-56T>G and c.-67G>C exhibited lower association with the polysomes suggestive of reduced mRNA translation efficiency [Bisio et al, 2010]. Work is being now extended to a panel of eleven additional germline variants in the 5'UTR of p16INK4a and the functional assays are being tailored towards a mechanistic understanding of their impact on mRNA stability and translation potential. In particular we are focusing on the functional interactions between wild-type and variant p16INK4a 5'- and 3'-UTR sequences and on the impact the variants can have on the targeting ofp16INK4a mRNA by microRNAs and RBPs.
* p53-miR-dependent post-transcriptional circuits: mechanisms, targets and inter-individual variation. A direct role of p53 on the activation of microRNA expression as well as a role on selective maturation of microRNA precursors has been recently established. Using custom pattern search approaches, the laboratory directed by Dr. Jegga (Cincinnati Children’s Hospital and University of Cincinnati) has identified an additional group of candidate microRNAs for direct p53 transcriptional control. To validate p53 family-mediated control of these newly predicted target miRs we are investigating the potential for wild type p53, p63 and p73 to transactivate from p53 response elements (REs) mapped at the miR promoters. This is being developed through yeast- and mammalian cell-based reporter assay as well as RTqPCR and ChIP assays. Our study is beginning to reveal additional miRs that could be directly regulated by the p53-family of transcription factors and could contribute to the tuning of p53-induced responses with the possibility of inter-individual variations due to functional SNPs.

Bisio A, Nasti S, Jordan JJ, Gargiulo S, Pastorino L, Provenzani A, Quattrone A, Queirolo P, Bianchi-Scarrà G, Ghiorzo P, Inga A. Functional analysis of CDKN2A/p16INK4a 5'-UTR variants predisposing to melanoma. Hum Mol Genet. 2010, 19, 1479-91
2. Ciribilli Y, Andreotti V, Menendez D, Langen JS, Schoenfelder G, Resnick MA, Inga A. The coordinated p53 and estrogen receptor cis-regulation at an FLT1 promoter SNP is specific to genotoxic stress and estrogenic compound. PLoS One. 2010; 5, e10236
3. Menendez D, Inga A, Resnick MA. Estrogen receptor acting in cis enhances WT and mutant p53 transactivation at canonical and noncanonical p53 target sequences. Proc Natl Acad Sci U S A. 2010, 107, 1500-5
4. Menendez D, Inga A, Resnick MA. Potentiating the p53 network. Discov Med. 2010; 10, 94-100.
5.Jordan JJ, Inga A, Conway K, Edmiston S, Carey LA, Wu L, Resnick MA. Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. Mol Cancer Res. 2010; 8, 701-16
6. Russo D, Ottaggio L, Penna I, Foggetti G, Fronza G, Inga A, Menichini P. PRIMA-1 cytotoxicity correlates with nucleolar localization and degradation of mutant p53 in breast cancer cells. Biochem Biophys Res Commun. 2010; 402, 345-50
7. Russo D, Fronza G, Ottaggio L, Monti P, Perfumo C, Inga A, Iyer P, Gold B, Menichini P. XRCC1 deficiency influences the cytotoxicity and the genomic instability induced by Me-lex, a specific inducer of N3-methyladenine. DNA Repair 2010; 9, 728-36.
8. Monti P, Traverso I, Casolari L, Menichini P, Inga A, Ottaggio L, Russo D, Iyer P, Gold B, Fronza G. Mutagenicity of N3-methyladenine: a multi-translesion polymerase affair. Mutat Res. 2010; 683, 50-6
9. Parodi S, Perfumo C, Garaventa A, Inga A, Mazzocco K, Defferrari R, Tonini GP, Fronza G, Haupt R. MDM2 SNP309 genotype is associated with ferritin and LDH serum levels in children with stage 4 neuroblastoma. Pediatr Blood Cancer. 2010, 55, 267-72
10. Menendez D, Inga A, Resnick MA. The expanding universe of p53 targets. Nat Rev Cancer. 2009;9, 724-37
11. Russo D, Fronza G, Ottaggio L, Monti P, Inga A, Iyer P, Gold B, Menichini P. High frequency of genomic deletions induced by Me-lex, a sequence selective N3-adenine methylating agent, at the Hprt locus in Chinese hamster ovary cells. Mutat Res. 2009; 671, 58-66
12. Reamon-Buettner SM, Ciribilli Y, Traverso I, Kuhls B, Inga A, Borlak J. A functional genetic study identifies HAND1 mutations in septation defects of the human heart. Hum Mol Genet. 2009; 18, 3567-78
13. Perfumo C, Parodi S, Mazzocco K, Defferrari R, Inga A, Scarrà GB, Ghiorzo P, Haupt R, Tonini GP, Fronza G. MDM2 SNP309 genotype influences survival of metastatic but not of localized neuroblastoma. Pediatr Blood Cancer. 2009; 53, 576-83
14. Capra V, Consales A, Nozza P, Monti P, Inga A, Fronza G.Identification of a novel TP53 germline mutation in a large Italian Li-Fraumeni syndrome Family. Pediatr Blood Cancer. 2009; 52, 303-4
15. Perfumo C, Parodi S, Mazzocco K, Defferrari R, Inga A, Haupt R, Fronza G, Tonini GP. Impact of MDM2 SNP309 genotype on progression and survival of stage 4 neuroblastoma. Eur J Cancer. 2008; 44,2634-9.
16. Jordan JJ, Menendez D, Inga A, Noureddine M, Bell DA, Resnick MA. Noncanonical DNA motifs as transactivation targets by wild type and mutant p53. PLoS Genet. 2008; 4, e1000104
17. Magrini R, Russo D, Ottaggio L, Fronza G, Inga A, Menichini P. PRIMA-1 synergizes with adriamycin to induce cell death in non-small cell lung cancer cells. J Cell Biochem. 2008; 104, 2363-73
18. Reamon-Buettner SM, Ciribilli Y, Inga A, Borlak J. A loss-of-function mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts. Hum Mol Genet. 2008; 17, 1397-405
19. Jegga AG*, Inga A*, Menendez D*, Aronow BJ, Resnick MA. Functional evolution of the p53 regulatory network through its target response elements. Proc Natl Acad Sci U S A. 2008; 105; 944-9
20. Monti P, Ciribilli Y, Russo D, Bisio A, Perfumo C, Andreotti V, Menichini P, Inga A, Huang X, Gold B, Fronza G. Rev1 and Polzeta influence toxicity and mutagenicity of Me-lex, a sequence selective N3-adenine methylating agent. DNA Repair 2008; 7, 431-8
21. Cardellino U, Ciribilli Y, Andreotti V, Modesto P, Menichini P, Fronza G, Pellegrino C, Inga A. Transcriptional properties of feline p53 and its tumour-associated mutants: a yeast-based approach. Mutagenesis. 2007, 22, 417-23.
Monti P, Ciribilli Y, Jordan J, Menichini P, Umbach DM, Resnick MA, Luzzatto L, Inga A*, Fronza G*. Transcriptional functionality of germ line p53 mutants influences cancer phenotype. Clin Cancer Res. 2007, 13, 3789-95
23. Menendez D*, Inga A*, Jordan JJ*, Resnick MA*. Changing the p53 master regulatory network: ELEMENTary, my dear Mr Watson. Oncogene. 2007; 26, 2191-201

No projects are available to students for the current accademic year.