Eijsink, M. (Marleen) (2012) DNA Interaction of the Progesterone Receptor is Critically Influenced by its Nuclear Matrix Targeting Signal. thesis, Medicine.
Full text available on request.Abstract
Breast cancer is the most common form of cancer amongst women and the main cause of death for women in the age of 40 to 59. Multiple studies have shown an increased risk of breast cancer after postmenopausal hormone treatment with a combined estrogen-progestin therapy. Understanding the mechanisms through which these steroids and their receptors operate, will give more insight in the development of cancer. The effects of progesterone are mediated by the progesterone receptor (PR), a nuclear transcription factor that binds directly to DNA and regulates the transcription of target genes. The progesterone receptor (PR) is expressed in two different isoforms: PRA and PRB. Where PRA is essential for uterine development and reproductive function, PRB is necessary for normal mammary gland development. In the breast progesterone controls mammary glands morphogenesis and has a proliferative function. DNA contains specific sequences, called progesterone response elements (PRE), which PR recognizes, binds to and has an increased sensibility for. In the classic and most common pathway of PR signaling, a receptor that is activated by progesterone, binds to DNA and regulates the transcription of genes. Binding result in a conformational change of the receptor and the formation of a receptor dimer (dimerization) and binding to the PRE. Binding to DNA leads to recruitment of coactivators and activation of the RNA polymerase II transcription apparatus. For appropriate regulation of gene transcription by PR, it is necessary that all different complexes involved in transcription follow the right set of events. In addition to local factors, also the nuclear localization of transcription factors are involved in the regulation of transcription. Active genes migrate to already assembled transcription sites, instead of recruiting and assembling the necessary transcription complexes. The mechanisms that regulate the recruitment of genes into these transcription sites expect to have a fundamental role in gene expression. Therefore also the nuclear positioning of PR and the trafficking signals that control this positioning into nuclear foci suggest to critically influence the transcriptional outcome. Nuclear matrix tethering of PR via its nuclear matrix targeting signal (NMTS) domain is suggested to be a critical event in the genomic interaction of PR, because it results in the appropriate nuclear localization of PR. This study showed that ablating the nuclear matrix targeting signal causes many fewer interactions of PR with DNA and lowers the specificity of PR genomic interactions. The mutated PR both binds and regulates less genes than the wild type PR. Most genes that do get bound by PR lacking a nuclear matrix targeting signal lose their regulation that is regardless of DNA binding. This suggested the loss of regulation was actually caused by inadequate nuclear positioning, due to ablating the nuclear matrix targeting sequence. Additionally PRB-NMTS fails to bind properly to PREs and binds more randomly to DNA. The study revealed that intra nuclear trafficking signals play a critical role in the genomic interactions of PR, which is relevant to its participation in appropriate regulation of gene transcription in normal breast cells, and which might be altered in breast malignancy.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Faculty Supervisor: and Schröder, Dr. C.P. |
| Supervisor name: | External supervisor: and Graham, Dr. D. and Westmead Institute for Cancer Research and University of Sydney Medical School - Westmead and NSW 2145 and Australia |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 10:39 |
| Last Modified: | 25 Jun 2020 10:39 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/76 |
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