Thesis (M.S.)--University of Michigan, 1965.

Thesis (M.S.)--University of Michigan, 1965.

Ph.D. / Molecular and Medical Genetics / The objective of this study is to examine, in light of the expression of multiple p53 family member isoforms, the specific role of p73 in malignant conversion, cellular response to DNA damage, and direct or indirect cooperation with other p53 family members in a clonal model of epidermal carcinogenesis. We first focused on the role of p73 in malignant conversion. Whether sporadic or siRNA induced, loss of p73 in initiated p53+/+ keratinocytes lead to conversion to squamous cell carcinoma (SCC) in vivo which was reversible upon reconstitution of TAp73α but not ΔNp73α. Second, we investigated the cellular response to ionizing radiation (IR) in the presence and absence of p73, showing that loss of p73 at malignant conversion was associated with resistance to IR in vitro. The loss of radiation sensitivity and malignant conversion was characterized by reduced steady state DNA binding levels of transcriptionally active p63 isoforms to the p21 promoter, failure to induce specific p53 family transcriptional targets, and failure to arrest in G1. Reconstitution of TAp73α, but not ΔNp73α, increased steady state DNA binding capabilities of TAp63β, TAp63γ, and ΔNp63γ, and steady state levels of p53 family target mRNA, but did not restore cellular sensitivity to IR. We thus uncovered a functional cooperation between TA isoforms of p73 and p63 and showed that p73-mediated DNA damage response was uncoupled from its tumor suppressive role. We observed preferential DNA binding of the inhibitory ΔNp63α isoform both in vitro and invivo in SCC suggesting that in the absence of TAp73α a balance is tipped toward DNA binding of the inhibitory isoforms. Third, we studied the role of the p53 family inkeratinocyte response to UVB. Tumorigenic cells lacking p73 that were resistant to IR remained sensitive to UVB, accompanied by DNA binding of the TAp63γ isoform, suggesting that keratinocyte response to UVB is not dependent upon p73 and suggesting a hierarchy of p53 family member responses to DNA damage. Finally, we examined TAp73α interaction with the p53 family inhibitor Mdm2. Mdm2 was in complex with DNA-bound p53 family members in malignant cells, but reconstitution of cells withTAp73α correlated with removal of Mdm2 from the complex, making them more like primary keratinocytes or initiated cells. Like the initiated cells, cells expressing TAp73α were refractory to treatment with the Mdm2-p53 inhibitor Nutlin-3 while cells lacking p73 expression or expressing ΔNp73α were sensitive. Thus, we suggest that p73 may be acting as a molecular shield to keep p53 family member inhibitors, such as ΔNp63α andMdm2, at bay. Further understanding of p53 family interplay in tumor development and DNA damage response could lead to new therapies or optimization of current therapeutic strategies in solid tumors of epithelium, particularly where deregulation or loss of p63 and p73 expression is associated with increased tumor invasiveness, treatment resistance, and poor patient prognosis.

196f. / Submitted by Suelen Reis (suziy.ellen@gmail.com) on 2013-04-10T17:24:12Z No. of bitstreams: 1 Disser Denize Silva.pdf: 10999494 bytes, checksum: 148c85bcd29a326b717b5cf519d96f68 (MD5) / Approved for entry into archive by Rodrigo Meirelles(rodrigomei@ufba.br) on 2013-04-22T19:25:07Z (GMT) No. of bitstreams: 1 Disser Denize Silva.pdf: 10999494 bytes, checksum: 148c85bcd29a326b717b5cf519d96f68 (MD5) / Made available in DSpace on 2013-04-22T19:25:07Z (GMT). No. of bitstreams: 1 Disser Denize Silva.pdf: 10999494 bytes, checksum: 148c85bcd29a326b717b5cf519d96f68 (MD5) Previous issue date: 2009 / As estações radiobase de telefonia celular têm sido estudadas quanto aos potenciais impactos à saúde ambiental. Esta dissertação tem como objetivo, analisar os condicionantes para licenciamentos de estações radiobase de telefonia celular. Para atingir este objetivo, analisou-se as condicionantes para licenciamento de estações radiobase de telefonia celular no município de Salvador, comparando-os a quatro municípios brasileiros de grande porte e ao Distrito Federal, bem como a análise da percepção dos atores que, direta ou indiretamente, se relacionam com o tema em estudo e participam do processo de licenciamento das ERBs. Utilizou-se como estratégias metodológicas,a pesquisa qualitativa em duas etapas. Na primeira, a pesquisa documental e na segunda etapa a pesquisa de campo realizada por meio de entrevista semi-estruturada, para analisar a percepção de profissionais, representantes de órgãos, operadoras e da população que reside e/ou trabalha até 400m da ERB. A legislação analisada mostrou fragilidades. Destacam-se ausências de condicionantes como audiência pública e limites restritivos para densidade de potência e distanciamento.A pesquisa realizada em campo indicou que a maioria da população entrevistada acredita ter sido prejudicada com a instalação das ERBs de telefonia celular próxima às suas residências. Dessa forma, os resultados levam ao entendimento de que há necessidade de se adotar condicionantes mais restritivos para o licenciamento de estações radiobase, de modo a contemplar o princípio da precaução. / Salvador