Luisa Guerrini
e-mail: luisa.guerrini AT unimi.it
affiliation: Università di Milano
research area(s): Cell Biology, Developmental Biology
Course:
Biomolecular Sciences
University/Istitution: Università di Milano
University/Istitution: Università di Milano
Luisa Guerrini
Born in Pavia, Italy- 11/11/1961
EDUCATION
1987 Laurea- Biological Sciences. Final grade 110/110.
Appointments
1985 to 1987
General Patology Dept., University of Napoli, Italy. Research student. Worked under the supervision of Prof. R. Di Lauro. Experimental work, construction of an inducible expression vector for eukaryotic cells to study the effects of forced expression of homeotic genes on cellular differentiation. During that time has also worked at the Dept of Biochemistry, N.I.H., Bethesda, (USA) supervised by Dr. M. Singer, from Aug 1985 to March 1986.
1988
Staff scientist at "Molecular Biology Laboratory", ENICHEM S.p.A., Monterotondo, Roma, Italy, directed by Prof. G. Tocchini- Valentini. Worked on the identification of ligands for muscarinic receptors.
1989 to 1992
Research Associate, laboratory of Prof. Claudio Basilico, Dept. of Microbiology, NYU School of Medicine, New York (USA). Worked on the transcriptional regulation of the human Asparagine Synthetase gene. This gene is regulated by intracellular aminoacid levels and is transcriptionally activated by aminoacid depletion; identification of cis and trans acting elements involved in this regulation.
1993 to 1995
AIRC fellowship- laboratory of Prof. Francesco Blasi, Dept of Genetics and Microrganisms Biology, University of Milano, Italy. Worked on the role played by the transcription factor Nf-kB in the regulation of the human urokinase gene in different cellular models.
1995 to 1999
Ricercatore Universitario BIO/11- Molecular Biology, Dept of Genetics and Microrganisms Biology , University of Milano, Italy, in the group of Prof. F. Blasi. Worked on the regulation/activation of the transcription factor NF-kB in cerebellar granule cells in colture: identification of the neurotrasmitter glutamate as the main inducer for NF-kb in these cells and in the mouse cerebellum development in vivo.
2000- Present
Ricercatore Universitario BIO/11- Molecular Biology , Dept Genetics and Microrganisms Biology, University of Milano, Italy- as independent group leader. Current research interest; unravelling the roles of the p63 transcrition factor during development.
Born in Pavia, Italy- 11/11/1961
EDUCATION
1987 Laurea- Biological Sciences. Final grade 110/110.
Appointments
1985 to 1987
General Patology Dept., University of Napoli, Italy. Research student. Worked under the supervision of Prof. R. Di Lauro. Experimental work, construction of an inducible expression vector for eukaryotic cells to study the effects of forced expression of homeotic genes on cellular differentiation. During that time has also worked at the Dept of Biochemistry, N.I.H., Bethesda, (USA) supervised by Dr. M. Singer, from Aug 1985 to March 1986.
1988
Staff scientist at "Molecular Biology Laboratory", ENICHEM S.p.A., Monterotondo, Roma, Italy, directed by Prof. G. Tocchini- Valentini. Worked on the identification of ligands for muscarinic receptors.
1989 to 1992
Research Associate, laboratory of Prof. Claudio Basilico, Dept. of Microbiology, NYU School of Medicine, New York (USA). Worked on the transcriptional regulation of the human Asparagine Synthetase gene. This gene is regulated by intracellular aminoacid levels and is transcriptionally activated by aminoacid depletion; identification of cis and trans acting elements involved in this regulation.
1993 to 1995
AIRC fellowship- laboratory of Prof. Francesco Blasi, Dept of Genetics and Microrganisms Biology, University of Milano, Italy. Worked on the role played by the transcription factor Nf-kB in the regulation of the human urokinase gene in different cellular models.
1995 to 1999
Ricercatore Universitario BIO/11- Molecular Biology, Dept of Genetics and Microrganisms Biology , University of Milano, Italy, in the group of Prof. F. Blasi. Worked on the regulation/activation of the transcription factor NF-kB in cerebellar granule cells in colture: identification of the neurotrasmitter glutamate as the main inducer for NF-kb in these cells and in the mouse cerebellum development in vivo.
2000- Present
Ricercatore Universitario BIO/11- Molecular Biology , Dept Genetics and Microrganisms Biology, University of Milano, Italy- as independent group leader. Current research interest; unravelling the roles of the p63 transcrition factor during development.
The p53/p63/p73 family
DNA damage elicit repair mechanisms involving the tumour suppressor gene p53. More recently, two additional members of the same family have been identified: p63 and p73. The molecular events driven by DNA damage to elicit the function of p63 is investigated in vitro. In parallel, the transcriptional activity of p63 is under scrutiny. The molecular mechanisms of apoptosis involving this gene is under investigation.
The role of p63 during mouse limb development is also currently being studied. The stability of the p63 protein is being investigated as well as how p63 natural mutations, associated to at least 5 different severe human developmental syndromes, alter p63 stability and functions. Protein interacting with p63 are in the process of being identified by a proteomic approach. Post-translational modifications regulating p63 activities are being identified by mass-spectrometry.
DNA damage elicit repair mechanisms involving the tumour suppressor gene p53. More recently, two additional members of the same family have been identified: p63 and p73. The molecular events driven by DNA damage to elicit the function of p63 is investigated in vitro. In parallel, the transcriptional activity of p63 is under scrutiny. The molecular mechanisms of apoptosis involving this gene is under investigation.
The role of p63 during mouse limb development is also currently being studied. The stability of the p63 protein is being investigated as well as how p63 natural mutations, associated to at least 5 different severe human developmental syndromes, alter p63 stability and functions. Protein interacting with p63 are in the process of being identified by a proteomic approach. Post-translational modifications regulating p63 activities are being identified by mass-spectrometry.
Guerrini L, Costanzo A, Merlo GR.A (2011) Symphony of Regulations Centered on
p63 to Control Development of Ectoderm-Derived Structures. Review- J Biomed Biotechnol. 2011;2011:864904
Lazzari C, Prodosmo A, Siepi F, Rinaldo C, Galli F, Gentileschi M, Bartolazzi A, Costanzo A, Sacchi A, Guerrini L, Soddu S. (2011) HIPK2 phosphorylates É¢Np63Éø and promotes its degradation in response to DNA damage. Oncogene. May 23.
Caratozzolo M., Micale L., Lopardo T., Galli F., Turturo M., Cornacchia S., Fusco C., Marzano F., Augello B., D’erchia A, Guerrini L., Pesole G., Sbisa E, Merla G., Tullo A. TRIM8 modulates p53 and DeltaNp63 alpha activity to dictate cell cycle arrest. Cancer Res- under revision
Botti E., Spallone G., Moretti F., Marinari B., Pinetti V., Galanti S., D'Onorio De Meo P., De Nicola F., Ganci F., Castrignanò F., Pesole G., Chimenti S., Guerrini L., Fanciulli M., Blandino G., Karin M., Costanzo A. The developmental factor IRF6 exhibits tumor suppressor activity in squamous cell carcinomas Proc: Natl Acad Scie
F Galli, M Rossi, Y D’Alessandra, M De Simone, T Lopardo, Y Haupt, O Alsheich-Bartok, S Anzi, E Shaulian, V Calabrò, G La Mantia L Guerrini. (2010) MDM2 and FBW7 cooperate to induce p63 protein degradation following DNA damage and cell differentiation- Journal of Cell Science 12:2423-33
F Moretti, B Marinari, N Lo Iacono, E Botti, A Giunta, G Spallone, E Vernesson, G Merlo, AA Mills, C Ballarò, S Alemà, S Chimenti, L Guerrini, A Costanzo.(2010). A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of two genetically different ectodermal dysplasias- Jour of Clinical Investigation;120(5):1570-7.
Amoresano A, Di Costanzo A, Leo G, Di Cunto F, La Mantia G, Guerrini L, Calabrò V. (2010). Identification of DeltaNp63alpha Protein Interactions by Mass Spectrometry. J Proteome Res.;9(4):2042-8.
Di Costanzo A, Festa L, Duverger O, Vivo M, Guerrini L, La Mantia G, Morasso MI, Calabrò V. (2009) Homeodomain protein Dlx3 induces phosphorylation-dependent p63 degradation. Cell Cycle. 15;8:1185-95.
Lopardo T., Lo Iacono N., Cyr D., Crosti F., Costanzo A., Guerrini L. (2008) Claudin-1 is a p63 target gene with a crucial role in epithelial development. Plos ONE- 23;3(7):e2715
Lo Iacono N., Mantero S., Chiarelli A., Garcia E., Mills A.A., Morasso M.I., Costanzo A., Levi G., Guerrini L, Merlo G.R. (2008). Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in the EEC and SHFM congenital limb defects. Development; 135: 1377-88. MERLO and GUERRINI co-senior authors
Radoja N, Guerrini L, Lo Iacono N, Merlo GR, Costanzo A, Weinberg WC, La Mantia G, Calabrò V, Morasso MI. (2007). Homeobox gene Dlx3 is regulated by p63 during ectoderm development: relevance in the pathogenesis of ectodermal dysplasias. Development;134:13-8.
Lanza M, Marinari B, Papoutsaki M, Giustizieri ML, D'Alessandra Y, Chimenti S, Guerrini L, Costanzo A. (2006) Cross-talks in the p53 family: deltaNp63 is an anti-apoptotic target for deltaNp73alpha and p53 gain-of-function mutants. Cell Cycle.5:1996-2004
Rossi M, De Simone M, Pollice A, Santoro R, La Mantia G, Guerrini L, Calabrò V. (2006). Itch/AIP4 associates with and promotes p63 protein degradation. Cell Cycle.5:1816-22.
Beretta C, Chiarelli A, Testoni B, Mantovani R, Guerrini L. (2005) Regulation of the cyclin-dependent kinase inhibitor p57Kip2 expression by p63. Cell Cycle.4:1625-31.
Ghioni P, D'Alessandra Y, Mansueto G, Jaffray E, Hay RT, La Mantia G, Guerrini L. (2005). The protein stability and transcriptional activity of p63alpha are regulated by SUMO-1 conjugation. Cell Cycle 4(1):183-90
Papoutsaki M, Moretti F, Lanza M, Marinari B, Sartorelli V, Guerrini L, Chimenti S, Levrero M, Costanzo A. (2005). A p38-dependent pathway regulates DeltaNp63 DNA binding to p53-dependent promoters in UV-induced apoptosis of keratinocytes. Oncogene.24:6970-5.
Calabrò V, Mansueto G, Santoro R, Gentilella A, Pollice A, Ghioni P, Guerrini L, La Mantia G. (2004). Inhibition of p63 transcriptional activity by p14ARF: functional and physical link between human ARF tumor suppressor and a member of the p53 family. Mol Cell Biol.;24:8529-40.
P. Ghioni, F. Bolognese, P. H.G. Duijf, H. van Bokhoven, R. Mantovani and L. Guerrini (2002). Complex transcriptional effects of p63 isoforms: identification of novel activation and repression domains. Mol. Cell. Biol. 22, 8659-8668.
p63 to Control Development of Ectoderm-Derived Structures. Review- J Biomed Biotechnol. 2011;2011:864904
Lazzari C, Prodosmo A, Siepi F, Rinaldo C, Galli F, Gentileschi M, Bartolazzi A, Costanzo A, Sacchi A, Guerrini L, Soddu S. (2011) HIPK2 phosphorylates É¢Np63Éø and promotes its degradation in response to DNA damage. Oncogene. May 23.
Caratozzolo M., Micale L., Lopardo T., Galli F., Turturo M., Cornacchia S., Fusco C., Marzano F., Augello B., D’erchia A, Guerrini L., Pesole G., Sbisa E, Merla G., Tullo A. TRIM8 modulates p53 and DeltaNp63 alpha activity to dictate cell cycle arrest. Cancer Res- under revision
Botti E., Spallone G., Moretti F., Marinari B., Pinetti V., Galanti S., D'Onorio De Meo P., De Nicola F., Ganci F., Castrignanò F., Pesole G., Chimenti S., Guerrini L., Fanciulli M., Blandino G., Karin M., Costanzo A. The developmental factor IRF6 exhibits tumor suppressor activity in squamous cell carcinomas Proc: Natl Acad Scie
F Galli, M Rossi, Y D’Alessandra, M De Simone, T Lopardo, Y Haupt, O Alsheich-Bartok, S Anzi, E Shaulian, V Calabrò, G La Mantia L Guerrini. (2010) MDM2 and FBW7 cooperate to induce p63 protein degradation following DNA damage and cell differentiation- Journal of Cell Science 12:2423-33
F Moretti, B Marinari, N Lo Iacono, E Botti, A Giunta, G Spallone, E Vernesson, G Merlo, AA Mills, C Ballarò, S Alemà, S Chimenti, L Guerrini, A Costanzo.(2010). A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of two genetically different ectodermal dysplasias- Jour of Clinical Investigation;120(5):1570-7.
Amoresano A, Di Costanzo A, Leo G, Di Cunto F, La Mantia G, Guerrini L, Calabrò V. (2010). Identification of DeltaNp63alpha Protein Interactions by Mass Spectrometry. J Proteome Res.;9(4):2042-8.
Di Costanzo A, Festa L, Duverger O, Vivo M, Guerrini L, La Mantia G, Morasso MI, Calabrò V. (2009) Homeodomain protein Dlx3 induces phosphorylation-dependent p63 degradation. Cell Cycle. 15;8:1185-95.
Lopardo T., Lo Iacono N., Cyr D., Crosti F., Costanzo A., Guerrini L. (2008) Claudin-1 is a p63 target gene with a crucial role in epithelial development. Plos ONE- 23;3(7):e2715
Lo Iacono N., Mantero S., Chiarelli A., Garcia E., Mills A.A., Morasso M.I., Costanzo A., Levi G., Guerrini L, Merlo G.R. (2008). Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in the EEC and SHFM congenital limb defects. Development; 135: 1377-88. MERLO and GUERRINI co-senior authors
Radoja N, Guerrini L, Lo Iacono N, Merlo GR, Costanzo A, Weinberg WC, La Mantia G, Calabrò V, Morasso MI. (2007). Homeobox gene Dlx3 is regulated by p63 during ectoderm development: relevance in the pathogenesis of ectodermal dysplasias. Development;134:13-8.
Lanza M, Marinari B, Papoutsaki M, Giustizieri ML, D'Alessandra Y, Chimenti S, Guerrini L, Costanzo A. (2006) Cross-talks in the p53 family: deltaNp63 is an anti-apoptotic target for deltaNp73alpha and p53 gain-of-function mutants. Cell Cycle.5:1996-2004
Rossi M, De Simone M, Pollice A, Santoro R, La Mantia G, Guerrini L, Calabrò V. (2006). Itch/AIP4 associates with and promotes p63 protein degradation. Cell Cycle.5:1816-22.
Beretta C, Chiarelli A, Testoni B, Mantovani R, Guerrini L. (2005) Regulation of the cyclin-dependent kinase inhibitor p57Kip2 expression by p63. Cell Cycle.4:1625-31.
Ghioni P, D'Alessandra Y, Mansueto G, Jaffray E, Hay RT, La Mantia G, Guerrini L. (2005). The protein stability and transcriptional activity of p63alpha are regulated by SUMO-1 conjugation. Cell Cycle 4(1):183-90
Papoutsaki M, Moretti F, Lanza M, Marinari B, Sartorelli V, Guerrini L, Chimenti S, Levrero M, Costanzo A. (2005). A p38-dependent pathway regulates DeltaNp63 DNA binding to p53-dependent promoters in UV-induced apoptosis of keratinocytes. Oncogene.24:6970-5.
Calabrò V, Mansueto G, Santoro R, Gentilella A, Pollice A, Ghioni P, Guerrini L, La Mantia G. (2004). Inhibition of p63 transcriptional activity by p14ARF: functional and physical link between human ARF tumor suppressor and a member of the p53 family. Mol Cell Biol.;24:8529-40.
P. Ghioni, F. Bolognese, P. H.G. Duijf, H. van Bokhoven, R. Mantovani and L. Guerrini (2002). Complex transcriptional effects of p63 isoforms: identification of novel activation and repression domains. Mol. Cell. Biol. 22, 8659-8668.
Project Title:
Project Title:
Unravelling the role of the cross-talk between the p63 transcription factor and the p300 acetylase
The transcription factor p63 is a key regulator of ectodermal, orofacial and limb development. In particular, it plays a critical role in epithelial biology, contributing to development and maintenance of the stratified epidermis (1). Dominant mutations in the p63 gene are causative of several human hereditary syndromes, such as AEC, EEC, LMS and SHFM-IV (2). Unequivocal establishment of the role of p63 in the pathogenesis of these human hereditary syndromes is complicated by the fact that this protein exists in multiple isoforms with different, often contradictory, biological activities. Moreover, the interrelationships between specific p63 isoforms and other members of the family (p53 and p73) play an essential role into the proliferation and differentiation programme of developing cells. Despite increasing knowledge about the biological function of p63 in the tissues in which is expressed, relatively little is known about the mechanisms governing the expression levels of the p63 proteins. The function played by p63 in ectodermal differentiation and stratified epithelial progenitor-cell maintenance is well assessed, however, further studies are required to determine the interplay of p63 with other signalling pathways including those regulating the other p53 family members.
It is likely that interrelationships between p53 and specific p63 isoforms play an essential role into the proliferation and differentiation programme of developing cells. A current opinion is that p63 and/or p73 reside with p53 in larger transcriptional complex in which each sibling may regulate the activity of the others (3). To this respect, mutations affecting the relative stability of specific isoforms might grossly alter the fine tuning of p53 and p63 activity on specific promoters.
It has already been demonstrated that one component of the principal p53 regulatory pathway, the p300 acetylase, is clearly involved also in the control of p73 isoforms (4, 5) with very little being known about its role on p63 isoforms (6).
We are now interested in unravelling the role of the p300 acetylase on p63 regulation during keratynocites differentiation and during mouse limb development.
The p300 acetylase has a critical role in regulating p53 and p73 protein stability and transcriptional activity. Recently, a new p300 site has been described in p53, lysine 164, which integrity is essential for p53 activities (7) that is perfectly conserved in p63 and is found mutated to glutamic acid (K193E) in patient affected by the SHFM-IV syndrome.
Interestingly, we have made preliminary observations suggesting that the effects of p300 on p63 stability could be affected by this natural mutation.
We intend now to better investigate the mechanisms through which p300 regulates p63 expression since, depending on their relative expression levels, p300 can mediate either p63 protein stabilization or p63 protein degradation. This dual role of p300 has already been described for the p53 protein (8).
Our studies should contribute to the identification of the molecular mechanisms and the cellular players involved in the control of epithelial and limb development and homeostasis.
Specific aims and workplan
The main objective of this Project is to investigate the role of the p300 protein and the molecular mechanisms with which it controls p63 protein stability, to understand how the physiological turnover of wild type and human syndromes-derived mutant p63 isoforms is regulated/deregulated, during mouse limb development and keratynocites differentiation, using different cell lines and primary and/or stabilized keratinocytes.
References
1) Barbieri CE, et al (2006) p63 and epithelial biology. Exp Cell Res 312, 695-706
2) Brunner HG, et al (2002) P63 gene mutations and human developmental syndromes. Am J Med Genet 112, 284-290
3) King KE, Weinberg WC.(2007) p63: defining roles in morphogenesis, homeostasis, and neoplasia of the epidermis. Mol Carcinog 46, 716-24
4)Barlev NA, Hiu L, Chehab NH, Mansfield K, Harris KG, Halazonetis TD and Berger SL. Acetylation of p53 Activates Transcrition trough Recruitment of Coactivators/Histone AcetylTransferase. Molecular Cell 2001; 8: 1243-1254
5) Mantovani F, Piazza S, Gostissa M, Stano S, Zacchi P, Mantovani R, Blandinoo G and Del Sal G. Pin1 Links the Activities of c-Abl and p300 in regulating p73 Function. Molecular Cell 2004; 14:625-636
6) MacPartlin M, Zeng S, Lee H, Stauffers D, Jin Y, Thayers M and Lu H. p300 regulates p63 Trasc-riptional Activity. The Journal of Biological Chemistry 2005; 280: 30604-30610.
7) Tang Y, Zhao W, Chen Y, Zhao Y and Gu W. Acetylation Is Indispensable for p53 Activation. Cell 2008; 133:612-626
8) Grossman SR, Deato ME, Brignone C, Man Chan H, Kung AL, Tagami H, Nakatani Y and Livingston DM. Polyubiquitination of p53 by a ubiquitin Ligase activity of p300. Science 2008; 300:342-344.
It is likely that interrelationships between p53 and specific p63 isoforms play an essential role into the proliferation and differentiation programme of developing cells. A current opinion is that p63 and/or p73 reside with p53 in larger transcriptional complex in which each sibling may regulate the activity of the others (3). To this respect, mutations affecting the relative stability of specific isoforms might grossly alter the fine tuning of p53 and p63 activity on specific promoters.
It has already been demonstrated that one component of the principal p53 regulatory pathway, the p300 acetylase, is clearly involved also in the control of p73 isoforms (4, 5) with very little being known about its role on p63 isoforms (6).
We are now interested in unravelling the role of the p300 acetylase on p63 regulation during keratynocites differentiation and during mouse limb development.
The p300 acetylase has a critical role in regulating p53 and p73 protein stability and transcriptional activity. Recently, a new p300 site has been described in p53, lysine 164, which integrity is essential for p53 activities (7) that is perfectly conserved in p63 and is found mutated to glutamic acid (K193E) in patient affected by the SHFM-IV syndrome.
Interestingly, we have made preliminary observations suggesting that the effects of p300 on p63 stability could be affected by this natural mutation.
We intend now to better investigate the mechanisms through which p300 regulates p63 expression since, depending on their relative expression levels, p300 can mediate either p63 protein stabilization or p63 protein degradation. This dual role of p300 has already been described for the p53 protein (8).
Our studies should contribute to the identification of the molecular mechanisms and the cellular players involved in the control of epithelial and limb development and homeostasis.
Specific aims and workplan
The main objective of this Project is to investigate the role of the p300 protein and the molecular mechanisms with which it controls p63 protein stability, to understand how the physiological turnover of wild type and human syndromes-derived mutant p63 isoforms is regulated/deregulated, during mouse limb development and keratynocites differentiation, using different cell lines and primary and/or stabilized keratinocytes.
References
1) Barbieri CE, et al (2006) p63 and epithelial biology. Exp Cell Res 312, 695-706
2) Brunner HG, et al (2002) P63 gene mutations and human developmental syndromes. Am J Med Genet 112, 284-290
3) King KE, Weinberg WC.(2007) p63: defining roles in morphogenesis, homeostasis, and neoplasia of the epidermis. Mol Carcinog 46, 716-24
4)Barlev NA, Hiu L, Chehab NH, Mansfield K, Harris KG, Halazonetis TD and Berger SL. Acetylation of p53 Activates Transcrition trough Recruitment of Coactivators/Histone AcetylTransferase. Molecular Cell 2001; 8: 1243-1254
5) Mantovani F, Piazza S, Gostissa M, Stano S, Zacchi P, Mantovani R, Blandinoo G and Del Sal G. Pin1 Links the Activities of c-Abl and p300 in regulating p73 Function. Molecular Cell 2004; 14:625-636
6) MacPartlin M, Zeng S, Lee H, Stauffers D, Jin Y, Thayers M and Lu H. p300 regulates p63 Trasc-riptional Activity. The Journal of Biological Chemistry 2005; 280: 30604-30610.
7) Tang Y, Zhao W, Chen Y, Zhao Y and Gu W. Acetylation Is Indispensable for p53 Activation. Cell 2008; 133:612-626
8) Grossman SR, Deato ME, Brignone C, Man Chan H, Kung AL, Tagami H, Nakatani Y and Livingston DM. Polyubiquitination of p53 by a ubiquitin Ligase activity of p300. Science 2008; 300:342-344.
Project Title:
A p63/ c-Abl
The p63 transcription factor, homolog to the p53 tumor suppressor, is involved in development, cell differentiation, tumor suppression and response to genotoxic stress. Expression of the p63 protein is essential for normal development of the limbs and all stratified ephitelia. p63 Knock-Out (KO) mice die of dehydration after birth with truncations of the limbs, no epidermis and craniofacial defects reflecting ectodermal stem cells loss.
p63 mutations are found in several human syndromes, including the Acro Dermato Ungueal Lacrimal Tooth (ADULT) syndrome. ADULT patients display exfoliative dermatitis of the digits (1). Two ADULT patients, carrying the p63 mutation R298Q, display Ectodermal Dysplasia (ED) and Paroxysmal supraventricular tachycardia: this disturbance, in the ADULT patients, could be a consequence of atriomegalia resulting from inadequate cell adherance mediated by desmosomes as observed in Arhytmogenic Right Ventricular Cardiomiophaty (ARVC) patients.
p63 plays a role in the assembly of desmosomal adhesive complexes and in enhancing the ability of diferrent tissues, including the cardiac tissue, to resist to mechanical stresses (2).
Cardiac defects have been observed in the c-Abl Knock Out (KO) mice. cAbl is an ubiquitously expressed nonreceptor tyrosine kinase that, upon DNA damage, affects p63 protein stability leading to activation of proapoptotic genes. c-Abl KO newborn mice, display dramatically enlarged heart that is the primary cause of perintal death (3).
Our preliminary data show that in the HaCaT human keratinocyte cell line, expressing endogenous DNp63a and c-Abl, silencing of cAbl expression results in reduction of the p63 protein levels, indicating an interplay between p63 and c-Abl. In the H1299 and HaCaT cell lines, p63 overexpression activates transcription of the endogenous c-Abl gene suggesting the existence of a positive feedback loop between p63 and c-Abl. Moreover, a c-Abl promoter reporter plasmid was activated by overexpression of wild type Dnp63alpha while, interestingly, mutant p63 protein had impaired transcriptional activation capacity on this promoter.
These observations point to feed-back loop acting on p63 and c-Abl and we want to verify if this loop has a physiological role in heart development.
Reference
1. Am J Med Genet 112 284-90 2002
2. Cell 120 843-56 2005
3. PNAS 3 1136-41 2010
p63 mutations are found in several human syndromes, including the Acro Dermato Ungueal Lacrimal Tooth (ADULT) syndrome. ADULT patients display exfoliative dermatitis of the digits (1). Two ADULT patients, carrying the p63 mutation R298Q, display Ectodermal Dysplasia (ED) and Paroxysmal supraventricular tachycardia: this disturbance, in the ADULT patients, could be a consequence of atriomegalia resulting from inadequate cell adherance mediated by desmosomes as observed in Arhytmogenic Right Ventricular Cardiomiophaty (ARVC) patients.
p63 plays a role in the assembly of desmosomal adhesive complexes and in enhancing the ability of diferrent tissues, including the cardiac tissue, to resist to mechanical stresses (2).
Cardiac defects have been observed in the c-Abl Knock Out (KO) mice. cAbl is an ubiquitously expressed nonreceptor tyrosine kinase that, upon DNA damage, affects p63 protein stability leading to activation of proapoptotic genes. c-Abl KO newborn mice, display dramatically enlarged heart that is the primary cause of perintal death (3).
Our preliminary data show that in the HaCaT human keratinocyte cell line, expressing endogenous DNp63a and c-Abl, silencing of cAbl expression results in reduction of the p63 protein levels, indicating an interplay between p63 and c-Abl. In the H1299 and HaCaT cell lines, p63 overexpression activates transcription of the endogenous c-Abl gene suggesting the existence of a positive feedback loop between p63 and c-Abl. Moreover, a c-Abl promoter reporter plasmid was activated by overexpression of wild type Dnp63alpha while, interestingly, mutant p63 protein had impaired transcriptional activation capacity on this promoter.
These observations point to feed-back loop acting on p63 and c-Abl and we want to verify if this loop has a physiological role in heart development.
Reference
1. Am J Med Genet 112 284-90 2002
2. Cell 120 843-56 2005
3. PNAS 3 1136-41 2010