Cyclin A1 Expression and Regulation in Hematopoietic and Leukemic Cells

Abstract

Increased expression of the cell cycle regulatory protein cyclin A1 has previously been detected in patients with acute myeloid leukemia (AML) and targeted overexpression of cyclin A1 in a transgenic mouse model initiated AML. The aim of this thesis was to further study the expression and regulation of cyclin A1 in hematopoietic cells. We started with evaluating the subcellular localization of cyclin A1 and found that the protein was localized to the nucleus of normal early hematopoietic cells while it had a cytoplasmic localization in leukemic bone marrow cells as well as in leukemic cell lines. We further found that treatment with all-trans retinoic acid (ATRA) resulted in nuclear localization of cyclin A1 in U-937 cells and in the formation of complex between cyclin A1, CDK1 and RAR?. Our results indicate that the cytoplasmic localization of cyclin A1 correlates with a leukemic phenotype. Next we continued with analyzing the clinical relevance of the increased cyclin A1 expression in 40 AML patients. We found that patients with high levels of cyclin A1 had a significantly worse overall survival and a significantly lower disease-free survival compared to patients with low levels of cyclin A1. We continued with analyzing the correlation between cyclin A1 and drug induced apoptosis. Induction of apoptosis using ATRA, staurosporine and TNF? resulted in significantly increased cyclin A1 protein levels in contrast to decreased levels of other cell cycle regulatory proteins. Interestingly, the increased protein levels did not result from increased protein synthesis but was rather a result from decreased ubiquitination and degradation. Further, upon overexpression of cyclin A1 a significant increased amount of apoptotic cells was found. Our results also suggest that there is an association between the post-translational modifications of cyclin A1 protein and the induction of apoptosis by therapeutic agents.

Abstract (Swedish)

Popular Abstract in Swedish

Man har tidigare sett att patienter med akut myeloisk leukemi (AML) har förhöjda nivåer av det cellcykelreglerande proteinet cyklin A1 och överuttryck av cyklin A1 i de myeloiska cellerna hos transgena möss resulterade i att mössen utvecklade AML. Syftet med avhandlingen var att ytterligare studera uttrycket och regleringen av cyklin A1 i hematopoetiska celler. Vi började med att utvärdera den subcellulära lokalisationen av cyklin A1 och vi fann att cyklin A1 fanns i kärnan hos normala hematopoetiska celler men befann sig huvudsakligen i cytoplasman hos leukemiska celler. Efter behandling av de leukemiska cellerna med all-trans retinoic acid (ATRA) hittade vi nu cyklin A1 i kärnan av de leukemiska cellerna och vi hittade även nya komplex mellan cyklin A1, CDK1 och RAR?. Våra resultat tyder på att den cytoplasmiska lokalisationen av cyklin A1 är kopplat till den leukemiska fenotypen. Vi fortsatte att analysera om cyklin A1 hade någon prognostisk betydelse hos 40 AML patienter. Vi upptäckte att patienter med höga nivåer av cyklin A1 i de leukemiska cellerna hade signifikant sämre överlevnad och högra frekvens av återfall än patienter med lägre nivåer av cyklin A1. Vi fortsatte att analysera om det fanns någon koppling mellan cyklin A1 och droginducerad apoptos. Induktion av apoptos med hjälp av ATRA, staurosporine och TNF? ledde till signifikant förhöjda protein nivåer av cyklin A1 till skillnad mot sänkta nivåerna av andra cellcykelreglerande proteiner efter drogbehandlingen. De ökade nivåerna av cyklin A1 proteinet var inte orsakade av ökad proteinsyntes utan berodde snarare minskad ubiquitinering och nedbrytning. Dessutom så ledde överutryck av cyklin A1 till ökade mängder apoptotiska celler. Våra resultat tyder på att det finns en koppling mellan post-translationell reglering av cyklin A1 och droginducerad apoptos.

• author: Ekberg, Jenny
• supervisor: Jenny L Persson; Göran Landberg
• opponent: Docent Öberg, Fredrik, Department of Genetics and Pathology, Uppsala University
• organization: Pathology, Malmö (research group)
• publishing date: 2006
• type: Thesis
• publication status: published
• subject: Cell and Molecular Biology; Cancer and Oncology
• keywords: cancer, General pathology, pathological anatomy, Patologi (allmän), patologisk anatomi, onkologi, Cytologi, cancerology, oncology, Cytology, AML, cyclin A1, apoptosis, cell cycle regulation
• in: Lund University Faculty of Medicine Doctoral Dissertation Series
• volume: 2006-30
• pages: 110 pages
• defense location: Main lecture hall, Pathology building, entrance 78, Malmö University Hospital, Malmö
• defense date: 2006-03-24 09:30:00
• ISSN: 1652-8220
• ISBN: 91-85481-55-6
• language: English
• LU publication?: yes
• additional info: J Ekberg, G Landberg, C Holm, J Richter, D Wolgemuth and J Liao Persson. 2004. Regulation of the cyclin A1 protein is associated with its differential subcellular localization in hematopoietic and leukemic cells. Oncogene,, vol 2;23 pp 9082-9.; J Ekberg, S Jalili, C Holm, J Richter, L Anagnostaki, G Landberg and J Liao Persson. 2005. Expression of cyclin A1 and cell cycle regulatory proteins in hematopoietic progenitors and acute myeloid leukemia and links to disease relapse and survival. European Journal of Haematology, vol 75 pp 106-15.; J Ekberg, C Brunhoff, M Järås, X Fan, G Landberg and J Liao Persson. . Increased expression of cyclin A1 protein is correlated with all-trans retinoic acid-induced apoptosis. International Journal of Biochemistry & Cell Biology, (accepted); J Ekberg, C Brunhoff, E Diffner, G Landberg and J Liao Persson. . Posttranslational modification of cyclin A1 is associated with staurosporine and TNFalpha induced apoptosis in leukemic cells. (manuscript)
• id: 89a420df-5b0b-4ce6-961e-6121e4882ee9 (old id 546378)
• date added to LUP: 2016-04-01 17:00:21
• date last changed: 2019-05-22 06:02:32