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The Role of TAp73 in Tumor Angiogenesis
Örebro universitet, Institutionen för naturvetenskap och teknik.
2013 (engelsk)Independent thesis Advanced level (degree of Master (Two Years)), 30 poäng / 45 hpOppgave
Abstract [en]

The p73 gene encodes two major classes of proteins; transactivation domain containing p73

(TAp73) isoforms that act as transcription factors and N-terminal truncated isoforms, ΔNp73,

that act in a dominant negative manner. p73 belongs to the p53-family of proteins and Ap73 shares many hallmark features with the archetypical tumor suppressor p53. However, in contrast to p53, p73 is rarely mutated and its tumorigenic effect may be due to the alteration in balance between TAp73 and ΔNp73 isoforms. To better comprehend how p73-isoforms control tumorigenesis in vivo, we generated E1A/RasV12G transformed TAp73+/+ and TAp73-/- mouse embryonic fibroblasts (MEFs) that were injected subcutaneously into Nude mice. We observed that TAp73-/- E1A/RasV12G MEFs formed larger tumors with shorter latency compared to TAp73+/+ E1A/RasV12G MEFs. Investigation of angiogenesis by immunohistochemical staining for the endothelial marker CD31 showed increased blood vessel formation in TAp73-/- tumors, this was further evaluated by in vitro HUVEC migration assay. Angiogenesis array analysis for genes that regulate angiogenesis revealed up-egulation of several pro-angiogenic targets namely CXCL2, CXCL5, CCL2, CCL11, IL-1β, IL6 and matrix metalloproteinase MMP2 in TAp73-/-tumors compared to wild type (WT). qRT-PCR analysis validated up-regulation of the proangiogenic cytokine IL-1β and chemokine CCL2 on mRNA level in TAp73-/- tumors. Since CCL2 is a macrophage chemo-attractant, we analyzed macrophage infiltration immunohistochemically and observed increased infiltration in TAp73-/- tumors compared to WT; furthermore, the effect on macrophage migration was also assessed by in vitro chemotaxis assay. Our data verify that TAp73 is a tumor suppressor and loss of TAp73 promotes angiogenesis; genes controlling angiogenesis and macrophage migration are up-regulated in absence of TAp73.

sted, utgiver, år, opplag, sider
2013. , s. 25
Emneord [en]
Tumor suppressors, pro-inflammatory chemokines, macrophages
HSV kategori
Identifikatorer
URN: urn:nbn:se:oru:diva-30355OAI: oai:DiVA.org:oru-30355DiVA, id: diva2:643809
Fag / kurs
Biology
Uppsök
Life Earth Science
Veileder
Examiner
Tilgjengelig fra: 2013-08-28 Laget: 2013-08-28 Sist oppdatert: 2017-10-17bibliografisk kontrollert

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