Proteome profiling of immortalization‐to‐senescence transition of human breast epithelial cells identified MAP2K3 as a senescence‐promoting protein which is downregulated in human breast cancer

Jia, Min; Souchelnytskyi, Nazariy; Hellman, Ulf; O’Hare, Michael J.; Jat, Parmjit; Souchelnytskyi, Serhiy

doi:10.1002/prca.201000006

Cited by 32 publications

(34 citation statements)

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“…Silver-stained protein spots were distributed in all areas of the pH gradient (pH 3-10), and an approximately even distribution was found for proteins in the range of molecular masses from 25 to 100 kDa. The overall distribution of proteins in 2-D gels was similar to proteome patterns observed for other human breast epithelial cells (Jia et al 2010;O'Hare et al 2001). Forty-five protein spots were observed as differentially expressed between cells cultured at 34°C and 39°C.…”

Section: Proteome Profilingsupporting

confidence: 72%

Proteome profiling of heat shock of human primary breast epithelial cells, a dataset report

Jia

Souchelnytskyi

2011

Cell Stress and Chaperones

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Exposure to elevated temperatures has a strong effect on cell functions, and is used in clinical practice. Hyperthermia may affect multiple regulatory mechanisms in cells. To understand better the response to hyperthermia of immortalized primary human breast epithelial cells, we performed a proteomics study of these cells cultured at 34°C or 39°C. Twenty-four proteins were shown to be differentially expressed due to hyperthermia. Analysis of these proteins showed the potential involvement of various biological processes in response to hyperthermia, e.g., cell adhesion, cell communication, and cell cycle. Transforming growth factor-β2 (TGF-β2) and heat shock protein 27 (HSP27) were found to be upregulated at 39°C. TGF-β2 was found to affect expression of HSP27, and to have a protective role in hyperthermia-induced cell death. Thus, the dataset described here of hyperthermia-related proteins in human primary breast epithelial cells predicts a number of cellular activities affected by exposure to high temperatures and provides a set of proteins for further studies.

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Section: Proteome Profilingsupporting

confidence: 72%

Proteome profiling of heat shock of human primary breast epithelial cells, a dataset report

Jia

Souchelnytskyi

2011

Cell Stress and Chaperones

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“…This protein was identified as a senescence-promoting factor in human breast epithelial cells [55]. However, it has also been associated to tumor invasion potential and to be regulated at transcriptional level by NFY, NF-κB and gain-of-function mutant p53 [56].…”

Section: Resultsmentioning

confidence: 99%

Whole-genome cartography of p53 response elements ranked on transactivation potential

et al. 2015

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BackgroundMany recent studies using ChIP-seq approaches cross-referenced to trascriptome data and also to potentially unbiased in vitro DNA binding selection experiments are detailing with increasing precision the p53-directed gene regulatory network that, nevertheless, is still expanding. However, most experiments have been conducted in established cell lines subjected to specific p53-inducing stimuli, both factors potentially biasing the results.ResultsWe developed p53retriever, a pattern search algorithm that maps p53 response elements (REs) and ranks them according to predicted transactivation potentials in five classes. Besides canonical, full site REs, we developed specific pattern searches for non-canonical half sites and 3/4 sites and show that they can mediate p53-dependent responsiveness of associated coding sequences. Using ENCODE data, we also mapped p53 REs in about 44,000 distant enhancers and identified a 16-fold enrichment for high activity REs within those sites in the comparison with genomic regions near transcriptional start sites (TSS). Predictions from our pattern search were cross-referenced to ChIP-seq, ChIP-exo, expression, and various literature data sources. Based on the mapping of predicted functional REs near TSS, we examined expression changes of thirteen genes as a function of different p53-inducing conditions, providing further evidence for PDE2A, GAS6, E2F7, APOBEC3H, KCTD1, TRIM32, DICER, HRAS, KITLG and TGFA p53-dependent regulation, while MAP2K3, DNAJA1 and potentially YAP1 were identified as new direct p53 target genes.ConclusionsWe provide a comprehensive annotation of canonical and non-canonical p53 REs in the human genome, ranked on predicted transactivation potential. We also establish or corroborate direct p53 transcriptional control of thirteen genes. The entire list of identified and functionally classified p53 REs near all UCSC-annotated genes and within ENCODE mapped enhancer elements is provided. Our approach is distinct from, and complementary to, existing methods designed to identify p53 response elements. p53retriever is available as an R package at: http://tomateba.github.io/p53retriever.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1643-9) contains supplementary material, which is available to authorized users.

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“…The MKK3 gene is located on chromosome 17p11.2, and recent proteome-profiling work has highlighted MKK3 as a senescence-promoting and generally downregulated protein in immortalized mammary epithelial cells (11), adding weight to the pursuit of mechanistic insight into the functional role of MKK3 activity in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

MAPK Kinase 3 Is a Tumor Suppressor with Reduced Copy Number in Breast Cancer

et al. 2014

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Cancers are initiated as a result of changes that occur in the genome. Identification of gains and losses in the structure and expression of tumor-suppressor genes and oncogenes lies at the root of the understanding of cancer cell biology. Here, we show that the mitogen-activated protein kinase (MAPK) MKK3 suppresses the growth of breast cancer, in which it varies in copy number. A pervasive loss of MKK3 gene copy number in patients with breast cancer is associated with an impairment of MKK3 expression and protein level in malignant tissues. To assess the functional role of MKK3 in breast cancer, we showed in an animal model that MKK3 activity is required for suppression of tumor growth. Active MKK3 enhanced expression of the cyclin-dependent kinase inhibitors p21Cip1/Waf1 and p27 Kip1 , leading to increased cell-cycle arrest in G 1 phase of the cell cycle. Our results reveal the functional significance of MKK3 as a tumor suppressor and improve understanding of the dynamic role of the MAPK pathway in tumor progression. Cancer Res; 74(1); 162-72. Ó2013 AACR.

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Proteome profiling of immortalization‐to‐senescence transition of human breast epithelial cells identified MAP2K3 as a senescence‐promoting protein which is downregulated in human breast cancer

Abstract: we described a proteome profile of the immortalization-to-senescence transition for human breast epithelial cells, and identified MAP2K3 as a protein that promotes senescence in these cells.

Cited by 32 publications

References 20 publications

Proteome profiling of heat shock of human primary breast epithelial cells, a dataset report

Proteome profiling of heat shock of human primary breast epithelial cells, a dataset report

Whole-genome cartography of p53 response elements ranked on transactivation potential

MAPK Kinase 3 Is a Tumor Suppressor with Reduced Copy Number in Breast Cancer

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