GSBS Dissertations and Theses

Approval Date

3-29-2013

Document Type

Doctoral Dissertation

Academic Program

Interdisciplinary Graduate Program

Department

Program in Molecular Medicine

First Thesis Advisor

Stephen Doxsey, PhD

Keywords

Autophagy, Cell Division, Cell Differentiation, Cell Cycle Proteins, Nuclear Proteins

Subjects

Dissertations, UMMS; Autophagy; Cell Division; Cell Differentiation; Cell Cycle Proteins; Nuclear Proteins

Abstract

The midbody (MB) is a proteinaceous complex formed between the two daughter cells during cell division and is required for the final cell separation event in late cytokinesis. After cell division, the post-mitotic midbody, or midbody derivative (MBd), can be retained and accumulated in a subpopulation of cancer cells and stem cells, but not in normal diploid differentiated cells. However, the mechanisms by which MBds accumulate and function are unclear. Based on this, I hypothesize that the MBd is degraded by autophagy after cell division in normal diploid differentiated cells, whereas non-differentiated cells have low autophagic activity and would accumulate MBds. Indeed, I found this to be the case. MBd degradation occurred soon after cytokinesis in differentiated cells that possess high autophagic activity. Specifically, I found MBd degradation to be mediated by binding of the autophagy receptor, NBR1, to the MB protein Cep55. Moreover, by performing proteomic analysis of NBR1 interactions I found additional MB-localized proteins that are potential substrates for NBR1. In contrast to differentiated cells, stem and cancer cells have low autophagic activity thus MBds evade autophagosome encapsulation and accumulate. To examine whether MBds can define the differentiation status of a cell, we depleted NBR1 from differentiated fibroblasts causing an increase in MBd number. Strikingly, under these conditions, reprogramming of fibroblasts to pluripotent stem cells is increased. Equally interestingly, cancer cells with increased MBds have increased in vitro tumorigenicity. In conclusion, this study gives an insight into the fates of post-mitotic midbodies and also suggests a non-cytokinetic role of midbodies in enhancing pluripotency in stem cells and cancer stem cells.

DOI

10.13028/M2MC75

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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