Leiden University Scholarly Publications

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Wolf, Cornelia de (2006)

Regulation of human protein S gene (PROS1) transcription

Doctoral Thesis
This thesis describes the investigation of the transcriptional regulation of the gene for anticoagulant plasma Protein S, PROS1. Protein S is a cofactor for Protein C in the Protein C anticoagulant pathway. The coagulation cascade is negatively regulated by this pathway through inactivation of activated clotting factors V and VIII. Protein S deficiency is associated with an increased risk for the development of deep venous thrombotic disease and the deficiency can either be hereditary or acquired. The presented research was mainly aimed at resolving several basic scientific issues regarding the regulation of transcription of PROS1. In Chapter 2 we identified 3 transcription start sites through which transcription is mainly driven. In chapters 3 and 4 we investigated which transcription factors are involved in PROS1 transcription. We found an interaction of several transcription factors with the Protein S gene promoter and showed that constitutive transcriptional activity is mainly...Show moreThis thesis describes the investigation of the transcriptional regulation of the gene for anticoagulant plasma Protein S, PROS1. Protein S is a cofactor for Protein C in the Protein C anticoagulant pathway. The coagulation cascade is negatively regulated by this pathway through inactivation of activated clotting factors V and VIII. Protein S deficiency is associated with an increased risk for the development of deep venous thrombotic disease and the deficiency can either be hereditary or acquired. The presented research was mainly aimed at resolving several basic scientific issues regarding the regulation of transcription of PROS1. In Chapter 2 we identified 3 transcription start sites through which transcription is mainly driven. In chapters 3 and 4 we investigated which transcription factors are involved in PROS1 transcription. We found an interaction of several transcription factors with the Protein S gene promoter and showed that constitutive transcriptional activity is mainly directed by transcription factor Sp1. Chapter 5 describes the regulation of Protein S levels by inflammatory mediator interleukin 6. The effect of interleukin 6 on Protein S levels was shown to be mediated though a direct interaction of transcription factor STAT3 with the Protein S gene promoter. In Chapter 6 an alternative PROS1 transcript is described. The protein that is generated from this transcript in vitro was shown not to be excreted from the cell but instead retained in the cell. Finally, our findings are discussed in Chapter 7.Show less
Protein S
Coagulation
PROS1
Sp1
Transcription
Transcription start site
All authors
Wolf, Cornelia de
Supervisor
Bertina, R.M.
Co-supervisor
Vos, H.L.
Qualification
Doctor (dr.)
Awarding Institution
Department of Hematology, Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Date
2006-05-29

Funding

Sponsorship
Trombose Stichting Nederland Dr. Ir. van de Laar Stichting