Transcription factors PROX1 and p53 in cancer development

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Oncology-Pathology

Sammanfattning: The majority of malignant brain tumors in adults are astrocytic gliomas. These are classified into four malignancy grades according to the World Health Organization (WHO) criteria, including grade I pilocytic astrocytoma, grade II astrocytoma, grade III anaplastic astrocytoma and grade IV glioblastoma. Understanding the underlying molecular defects of these tumors gives us the possibility to design new effective therapies. PROX1 is a transcription factor that has an important role in the developmental process of various organs during embryogenesis, including the central nervous system. In paper I we examined a group of 56 paraffin embedded astrocytic brain tumors for their expression of PROX1. We found that the number of PROX1+ cells was correlated to high tumor grade. We concluded that PROX1 maybe used as a diagnostic tool distinguishing between grade III, IV tumors and grade II astrocytomas. This finding led us to investigate PROX1 s prognostic and predictive value in grade II tumors, because these tumors have a highly unpredictable course of progression to a more malignant grade, which hinders the clinicians choice of treatment. In paper II we studied the expression levels of PROX1 in 128 grade II astrocytic brain tumors and found that it is a highly dependable, predictive factor for short term survival in patients with astrocytic gliomas but not for oligodendrogliomas. We propose that in the future PROX1 maybe used in the clinical routine as a biomarker to help in prediction of prognosis for astrocytic brain tumors. In order to understand why PROX1 is up regulated in these tumors, we determined its expression in different established glioma cell lines, to serve as a tool for the functional studies of the protein (paper III). A hallmark of glioblastoma is mutations in the p53 tumor suppressor gene. p53 is also frequently mutated in other tumors including those from lung, breast and skin. In paper IV we used a mouse skin model, p53QS-val135/QS-val135 (p53QS), to examine the importance of p53 transcriptional regulatory function in tumor suppression. This model contains a double mutationin the N-terminus of p53 abrogating the transactivation domain and a modification at amino acid 135 partially affecting DNA binding. Ras oncogene-induced senescence was lost in both p53QS and p53-/- keratinocytes. Likewise, p53QS, similar to p53-/-, cooperated with v-rasHa to enhance malignant conversion. The tumors arising in p53QS keratinocytes displayed strong nuclear p53 expression, thus the p53QS-val135 allele was maintained during tumor formation. While p53-/- keratinocytes displayed diminished response to TGF-beta, p53QS and p53wt keratinocytes responded equivalently, indicating that the requirement of p53 for maximizing TGF-beta-mediated growth regulation is independent of its transactivation domain and that TGF-beta-mediated growth regulation is not required for p53 mediated tumor suppression in the skin.

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