Caspase 3 Disrupts the Pluripotency of Embryonic Stem Cells

Network Image

This network was generated using Cytoscape V2.2, yFiles/circular layout with a lexically-driven XML plug-in to the Agilent Literature Search, curated and color coded in Adobe Illustrator CS2.

Embryonic stem cells (ESCs) are capable of indefinite self-renewal while retaining the ability to differentiate. An emerging view is that a core set of transcription factors form a robust auto-regulatory circuit that maintains ES cells in a self-renewing state. ES cells may retain the capacity for rapid differentiation by post-translational modification. Attractive candidates for the role of post-translational modifiers of ES cell function are the site-specific proteases of the programmed cell death system.

The cysteine protease caspase 3 (casp3, node in yellow) is especially notable because it not only cleaves vital proteins, but also activates other caspases, such as caspase 9, that have their own targets. These proteases are very specific for particular amino acid sequences, are highly regulated in their activities, and in some contexts appear to influence the decision of cells to differentiate as well as being executioners of cell death programs.

We have been annotating all published proteolytic event for caspase 3 and have identified a total of 847 caspase 3 mediated proteolytic events (see CutDB entries in this web site). Most of these cleavage events are not captured by Gene Ontology and therefore their edges are not presented in this network. However, a few notable CutDB-substrates can be seen in the vicinity of Casp3 such as ..catenin, bcl2, tp53, brca1, pkc, atm and akt1, as well as many at a distance such as actin, twist1, notch1, krt15 and creb1 (nodes in bright green).

In this network, a total of 307 nodes that were captured from 674 publications, associated to Nanog and/or Oct4, which is a POU domain.containing transcription factor encoded by Pou5f1; more than one-fourth (>70) of these proteins are transcription factors (blue nodes) and several are signaling molecules (purple nodes) or related to phosphorylation events (orange nodes). The average number of edges per node is 3.32. Nanog and Oct4 play a decisive role in maintaining pluripotency of ESCs. Cells lacking the activity of the Oct4 and Nanog genes undergo differentiation into derivatives of extraembryonic endoderm and trophectoderm.

Our observation suggests that ESCs exploit caspase 3 for rapid and specific deactivation of Nanog and other key proteins from the circuit, thus disrupting the auto-regulatory circuit that otherwise preserves pluripotency in these cells. Thus, caspase 3 may play a dominant role in this negative regulation, by acting directly on Nanog or by interacting as a cofactor with caspase 9, which then deactivates the transcription factor and other targets.

Below are links to NCBI by PMID supporting this network.

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