Systems biology of mitosis [Elektronische Ressource] / by Bashar Ibrahim

Bashar Ibrahim [e-mail]

Sujets

• Biologie

Informations

• Publié par: friedrich-schiller-universitat_jena
• Publié le: 01 janvier 2008
• Nombre de lectures: 42
• Langue: English
• Poids de l'ouvrage: 8 Mo

Extrait

Systems Biology of Mitosis
Dissertation
to receive the degree Dr. rer. nat from the
Friedrich-Schiller-University Jena
by
Bashar Ibrahim
Born on August 28, 1976 in MosulExaminers:
1. PD Dr. Peter Dittrich (Jena Centre for Bioinformatics & FSU Jena)
2. Prof. Dr. Stephan Diekmann (Fritz-Lipmann-Institute Jena)
3. Dr. Andrea Musacchio (European Institute of Oncology)
Oral examination : July 30, 2008
Public defence : September 15, 2008Systems Biologie der Mitose
Dissertation zur Erlangung des akademischen Grades doctor rerum
naturalium (Dr. rer. nat.) vorgelegt dem Rat der Fakult at fur
Mathematik und Informatik der Friedrich-Schiller-Universit at Jena
von
Bashar Ibrahim
geboren am 28.08.1976 in MosulGedruckt mit Unterstutzung des Deutschen Akademischen Austauschdienstes
Gutachter:
1. PD Dr. Peter Dittrich (Jenaer Centrum fur Bioinformatik & FSU Jena)
2. Prof. Dr. Stephan Diekmann (Fritz-Lipmann-Institut Jena)
3. Dr. Andrea Musacchio (Europ aisch Institut fur Onkologie)
Tag der letzten Prufung des Rigorosums: 30. Juli 2008
Tag der o en tlichen Verteidigung: 15. September 2008To the loving memory of my Father,
thwho passed away on March 14 , 2005.
I’ve no words to describe him.
I am so proud of his gentle, beautiful ways.
I did see his love. He presented me with it, and it lled my
heart with loyalty and dignity.
I dedicate this work to him, to honor these lial remem-
brances.
... And to my Mother.
Her support, encouragement, and constant love have sus-
tained me throughout my entire life.Acknowledgements
I am deeply indebted to the German Academic Exchange Service
(DAAD) for providing me with a high-quality research opportunity to
carry out my PhD research in Germany.
I would like to express my gratitude to my advisor, Peter Dittrich,
whose research expertise, comprehensive understanding of our work,
and patience, added considerable knowledge to my graduate experience.
I am most thankful, and indebted to him in all possible ways.
Stephan Diekmann made crucial contributions in the context of this
thesis. He became a virtual co-adviser of my research, and provided
us with critical knowledge on all the biological aspects of this work.
I am grateful to Eberhard Schmitt for his important and very much
welcomed contributions on many mathematical aspects of this work.
I would also like to thank Clemens Beckstein for his unconditional
support to our work.
My sincere thanks also go to Rodulf Goren o and Martin Hermann,
who initially supported my research, and to Mrs. Margret Steuernagel
and Mrs. Birgit Klaes (DAAD), who took care of many important
aspects related to my wonderful experience in Germany.
I would like to express my profound gratitude to my friends, Mariana
Gil and Rodrigo De Marco; their extraordinary love and support were
of immeasurable value to me.
I feel a deep sense of gratitude to my family who formed part of my
vision and taught me the good things that really matter in life. The
happy memory of my father still provides a persistent inspiration formy journey in this life. I am grateful for my beloved brothers for
rendering me the sense and the value of brotherhood. I am glad to be
one of them.
Finally, it is my belief that quite a number of people contributed to
and supported my work in many di erent ways. It would virtually be
impossible to refer to all of them, and to emphasize their roles and
speci c contributions. They will, I think forgive me if I name only
the two whose contribution proved most far-reaching and decisive:
Thorsten Lenser and Heiko Lochas.Abstract
In mitosis, ‘surveillance control mechanisms’ regulate transitions across
the several stages of cell division. The so called ‘Mitotic-Spindle-
MAssembly-Checkpoint ( SAC)’ and ‘Exit-From-Mitosis (EFM)’ are
Mexamples of such mechanisms. SAC ensures the correct segregation
of chromosomes by preventing cell-cycle progression until all chromo-
somes have made proper bipolar attachments to the mitotic spindle
through their kinetochores. EFM ensures that each of the two daughter
nuclei receives one copy of each chromosome. Both mechanisms are
seemingly regulated by the so called ‘Anaphase-Promoting-Complex
(APC)’, bound, in turn, to either ‘Cdc20’ or ‘Cdh1’, which are asso-
ciated regulatory proteins. APC remains inactive during metaphase.
In the transition from metaphase to anaphase, and only after all
chromosomes are attached, a newly formed ‘APC:Cdc20’ complex
mediates the ubiquitination and degradation of the protein ‘Securin’;
this leads, in turn, to the activation of the protein ‘Separase’, the
dissolution of the so called ‘Cohesin Complex’, and, eventually, to
chromatid separation. ‘APC:Cdc20’ also mediates the initial phase of
‘Cyclin B’ proteolysis. In the transition from anaphase to telophase,
APC:Cdh1 completely ubiquitinates ‘Cyclin B’, thus inactivating a pro-
tein called ‘CyclinB:Cdk1-Mitotic-Kinase’ and triggering the exit from
Mmitosis. Both SAC and EFM prevent chromosome miss-segregation
and aneuploidy, and their failure eventually leads to cell death; both
mechanisms have been implicated in cancer. Our understanding of
mitotic regulatory mechanisms has signi cantly improved in recent
Myears. Yet, SAC and EFM remain poorly understood. Hence, we
bene ted from in-silico modeling and simulation approaches embed-
ded in a cross-disciplinary framework, typically referred to as SystemsBiology, in order to contribute to a deeper understanding of these
mitotic regulatory mechanisms. We rst focused on the question how
‘Cdc20’ availability is controlled prior to the attachments of all chro-
mosomes; or, in other words, how ‘APC:Cdc20’ formation is eventually
prevented. It had been proposed that Cdc20 remains fully sequestered
until the last chromosome is attached. By using a Systems Biology
approach to this question, we built-up and tested predictions from
a series of dynamic models fed with empirical data (Ibrahim et al.,
2008b,c). According to our results, cells are unable to completely
sequester Cdc20 until the last chromosome is attached. Next, we
asked whether a complex called ‘MCC’ might be able to fully prevent
‘APC:Cdc20’ formation by binding APC, thereby sequestering it fully,
prior to the attachment of all chromosomes. To tackle this question,
we built-up a combined in-silico model fed with empirical data on
APC levels prior to chromosome attachment (Ibrahim et al., 2008a).
Our results then showed that MCC can fully sequester APC prior to
chromosome attachment. This would eventually prevent ‘APC:Cdc20’
activity. From the later results, one still needs to ask how a complex
like ‘MCC:APC’ would fall apart after chromosome attachment. In
order to address this question, we constructed two equally suitable
model variants, called the \Dissociation" and \Convey" models, and
validated them by means of mutation experiments (Ibrahim et al.,
2008a). Moreover, we also developed and tested the robustness of a
Mqualitative model of SAC (Ibrahim et al., 2007). Finally, we incorpo-
rated an adapted ‘EFM-model’ involving ‘APC:Cdh1’ activity into an
integrative model involving APC:Ccd20 activity, thereby addressing
simultaneously the functioning of both transition control mechanisms,
MSAC and EFM.