Journal article
Impact of p21 Knockout on Topotecan-Induced Stress Responses in Human Colon Carcinoma Cells: A Proteomic Analysis
The open proteomics journal, Vol.2, pp.30-39
01/01/2009
Handle:
https://hdl.handle.net/2376/113471
Abstract
There are few reports describing the role of p21-dependent protein repression in cell death. To identify such cell death-associated proteins and to shed the light into the molecular mechanisms by which p21 is responding to pharmacological stress, we used a subcellular proteomic approach for the analysis of protein expression profiles of fractionated nuclei, mitochondria, and cytosols of isogenic p21 null (p21-/-) and wild-type human HCT-116 cells following treatment with sublethal doses (1[mu]M) of the topoisomerase I inhibitor, topotecan (TPT). In total, 174 unique deregulated proteins were identified in HCT-116 cells following treatment with TPT, whereas only 146 proteins were identified in p21-/- cells. They contributed to multiple functional activities of stress signaling pathways, and that p21-/- cells are accelerated to be more responsive to topotecan-induced cell death due to the following: 1) down regulation of proteins involved in the transcriptional and replication machinery of cells like DNA (cytosine-5)-methyltransferase 1, Matrin 3, DNA replication licensing factor MCM4, heterogeneous nuclear ribonucleoprotein Q, poly(Rc)-binding protein 1 and splicing factor arginine serine rich 7; 2) the activation of a caspase-independent apoptosis by the upregulation of the Bcl2 inhibitor of transcription (Bit1) protein; and 3) the activation of TNF alpha signaling by the upregulation of macrophage immigration inhibitory factor (MIF), and 26S proteosome non-ATPase regulatory subunit 2 (TRAP2) proteins. We suggest that the upregulation of these proteins are contributing factors to the molecular mechanisms of topotecan- induced cell death in p21-/- cells; and that the data present an opportunity for developing new therapeutic approaches for selective targeting of p21- signaling pathways.
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Details
- Title
- Impact of p21 Knockout on Topotecan-Induced Stress Responses in Human Colon Carcinoma Cells: A Proteomic Analysis
- Creators
- Kyunghee LeeSayed S Daoud
- Publication Details
- The open proteomics journal, Vol.2, pp.30-39
- Academic Unit
- Pharmaceutical Sciences, Department of
- Identifiers
- 99900547974601842
- Language
- English
- Resource Type
- Journal article