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Cyclin A1 Expression and Regulation in Hematopoietic and Leukemic Cells

Ekberg, Jenny (2006) In Lund University Faculty of Medicine Doctoral Dissertation Series 2006-30.
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... (More)
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. (Less)
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Docent Öberg, Fredrik, Department of Genetics and Pathology, Uppsala University
organization
publishing date
type
Thesis
publication status
published
subject
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
publisher
KFS AB
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
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
@phdthesis{89a420df-5b0b-4ce6-961e-6121e4882ee9,
  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.},
  author       = {Ekberg, Jenny},
  isbn         = {91-85481-55-6},
  issn         = {1652-8220},
  language     = {eng},
  publisher    = {KFS AB},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Cyclin A1 Expression and Regulation in Hematopoietic and Leukemic Cells},
  volume       = {2006-30},
  year         = {2006},
}