Active Transport Can Greatly Enhance Cdc20:Mad2 Formation

Abstract

To guarantee genomic integrity and viability, the cell must ensure proper distribution of the replicated chromosomes among the two daughter cells in mitosis. The mitotic spindle assembly checkpoint (SAC) is a central regulatory mechanism to achieve this goal. A dysfunction of this checkpoint may lead to aneuploidy and likely contributes to the development of cancer. Kinetochores of unattached or misaligned chromosomes are thought to generate a diffusible “wait-anaphase” signal, which is the basis for downstream events to inhibit the anaphase promoting complex/cyclosome (APC/C). The rate of Cdc20:C-Mad2 complex formation at the kinetochore is a key regulatory factor in the context of APC/C inhibition. Computer simulations of a quantitative SAC model show that the formation of Cdc20:C-Mad2 is too slow for checkpoint maintenance when cytosolic O-Mad2 has to encounter kinetochores by diffusion alone. Here, we show that an active transport of O-Mad2 towards the spindle mid-zone increases the efficiency of Mad2-activation. Our in-silico data indicate that this mechanism can greatly enhance the formation of Cdc20:Mad2 and furthermore gives an explanation on how the “wait-anaphase” signal can dissolve abruptly within a short time. Our results help to understand parts of the SAC mechanism that remain unclear.

Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

“…They found that a diffusible signal can generally account for checkpoint operation. A more comprehensive model of the human SAC, including the Mad2 and BubR1 pathway, has been proposed by Ibrahim et al (2008a;2008b, 2009Ibrahim and Henze, 2014). A mathematical model for checkpoint activation based on the ''Mad2 template'' model by De Antoni et al (2005) is supported with in vitro experiments by Simonetta et al (2009).…”

“…So far, mathematical models have helped to elucidate the kinetochore structure and with that the mitotic checkpoint mechanism (Doncic et al, 2005;Görlich et al, 2014;Ibrahim et al, 2007;2008b;Ibrahim and Henze, 2014;Kreyssig et al, 2012;Lohel et al, 2009;Sear and Howard, 2006;Simonetta et al, 2009;Tschernyschkow et al, 2013). However, none of these models consider the APC regulatory pathways.…”

“…2 · 10 -2 s -1 (Ibrahim et al 2008b, Ibrahim andHenze, 2014) ( Eytan et al 2008), this study Other species start from zero 296 IBRAHIM theoretical point of view (Ibrahim et al, 2008b).This loop was therefore not considered in the model. For integrity, the biochemical equations of the autocatalytic amplification are listed by reaction (R4)-(R5) (see chemical reaction scheme, below).…”

A Mathematical Framework for Kinetochore-Driven Activation Feedback in the Mitotic Checkpoint

“…The operator ∇ refers to the spatial gradient in spherical coordinates ( ∇(r, θ, ϕ) = ∂ ∂r e r + 1 r ∂ ∂θ e θ + 1 rsin(θ) ∂ ∂ϕ e ϕ ). Recent mathematical models of the SAC mechanism show that spherical symmetry can be used without loss of generality [27,20], and this form is used here. The system in Eq.…”

“…Also, the different components often interact nonlinearly in space and time, and in the presence of various feedback loops, which lead to remarkable phenomena that are difficult to predict [15,28,36,16,14,61]. Mathematical models have helped to illuminate fundamental modules of the SAC controls [8,53,21,40,20,22,27,45,37,25,13,24,26,29,3]. These models yet conceived SAC activation on details molecular level in order to distinguish between different pathways.…”