Publications by authors named "Kelsey Wertzler"

4 Publications

  • Page 1 of 1

HMGA1 levels influence mitochondrial function and mitochondrial DNA repair efficiency.

Mol Cell Biol 2009 Oct 17;29(20):5426-40. Epub 2009 Aug 17.

School of Molecular Biosciences, Washington State University, Biotechnology/Life Sciences Bldg., Rm. 143, Pullman, WA 99164-4660, USA.

HMGA chromatin proteins, a family of gene regulatory factors found at only low concentrations in normal cells, are almost universally overexpressed in cancer cells. HMGA proteins are located in the nuclei of normal cells except during the late S/G(2) phases of the cell cycle, when HMGA1, one of the members of the family, reversibly migrates to the mitochondria, where it binds to mitochondrial DNA (mtDNA). In many cancer cells, this controlled shuttling is lost and HMGA1 is found in mitochondria throughout the cell cycle. To investigate the effects of HMGA1 on mitochondria, we employed a genetically engineered line of human MCF-7 cells in which the levels of transgenic HMGA1 protein could be reversibly controlled. "Turn-ON" and "turn-OFF" time course experiments were performed with these cells to either increase or decrease intracellular HMGA1 levels, and various mitochondrial changes were monitored. Results demonstrated that changes in both mtDNA levels and mitochondrial mass inversely paralleled changes in HMGA1 concentrations, strongly implicating HMGA1 in the regulation of these parameters. Additionally, the level of cellular reactive oxygen species (ROS) increased and the efficiency of repair of oxidatively damaged mtDNA decreased as consequences of elevated HMGA1 expression. Increased ROS levels and reduced repair efficiency in HMGA1-overexpressing cells likely contribute to the increased occurrence of mutations in mtDNA frequently observed in cancer cells.
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http://dx.doi.org/10.1128/MCB.00105-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756874PMC
October 2009

The high-mobility group A1a/signal transducer and activator of transcription-3 axis: an achilles heel for hematopoietic malignancies?

Cancer Res 2008 Dec;68(24):10121-7

Departments of Medicine, Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Although HMGA1 (high-mobility group A1; formerly HMG-I/Y) is an oncogene that is widely overexpressed in aggressive cancers, the molecular mechanisms underlying transformation by HMGA1 are only beginning to emerge. HMGA1 encodes the HMGA1a and HMGA1b protein isoforms, which function in regulating gene expression. To determine how HMGA1 leads to neoplastic transformation, we looked for genes regulated by HMGA1 using gene expression profile analysis. Here, we show that the STAT3 gene, which encodes the signaling molecule signal transducer and activator of transcription 3 (STAT3), is a critical downstream target of HMGA1a. STAT3 mRNA and protein are up-regulated in fibroblasts overexpressing HMGA1a and activated STAT3 recapitulates the transforming activity of HMGA1a in fibroblasts. HMGA1a also binds directly to a conserved region of the STAT3 promoter in vivo in human leukemia cells by chromatin immunoprecipitation and activates transcription of the STAT3 promoter in transfection experiments. To determine if this pathway contributes to HMGA1-mediated transformation, we investigated STAT3 expression in our HMGA1a transgenic mice, all of which developed aggressive lymphoid malignancy. STAT3 expression was increased in the leukemia cells from our transgenics but not in control cells. Blocking STAT3 function induced apoptosis in the transgenic leukemia cells but not in controls. In primary human leukemia samples, there was a positive correlation between HMGA1a and STAT3 mRNA. Moreover, blocking STAT3 function in human leukemia or lymphoma cells led to decreased cellular motility and foci formation. Our results show that the HMGA1a-STAT3 axis is a potential Achilles heel that could be exploited therapeutically in hematopoietic and other malignancies overexpressing HMGA1a.
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http://dx.doi.org/10.1158/0008-5472.CAN-08-2121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913892PMC
December 2008

Y-specific sequences and polymorphisms in rainbow trout and Chinook salmon.

Genome 2008 Sep;51(9):739-48

School of Biological Sciences and Center for Reproductive Biology, Washington State University, Pullman, WA 99164-4236, USA.

Improved methods for genetically sexing salmonids and for characterization of Y-chromosome homologies between species can contribute to understanding the evolution of sex chromosomes and sex-determining mechanisms. In this study we have explored 12.5 kb of Y-chromosome-specific sequence flanking the previously described OtY2 locus in Chinook salmon (Oncorhynchus tshawytscha) and 21 kb of homologous rainbow trout (Oncorhynchus mykiss) Y-chromosome-specific sequence. This is the first confirmed Y-specific sequence for rainbow trout. New Y-specific markers are described for Chinook salmon (OtY3) and rainbow trout (OmyY1), which are readily detected by PCR assays and are advantageous because they also produce autosomal control amplification products. Additionally, AFLP analysis of Chinook salmon yielded another potential Y-chromosome marker. These descriptions will facilitate genotypic sexing and should be useful for population studies of Y-chromosome polymorphisms and for future studies to characterize what appears to be a common sex-determining mechanism between these species.
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http://dx.doi.org/10.1139/G08-060DOI Listing
September 2008

High-mobility group A1 proteins inhibit expression of nucleotide excision repair factor xeroderma pigmentosum group A.

Cancer Res 2007 Jul;67(13):6044-52

School of Molecular Biosciences, Washington State University, Pullman, Washington 99164-4660, USA.

Cells that overexpress high-mobility group A1 (HMGA1) proteins exhibit deficient nucleotide excision repair (NER) after exposure to DNA-damaging agents, a condition ameliorated by artificially lowering intracellular levels of these nonhistone proteins. One possible mechanism for this NER inhibition is down-regulation of proteins involved in NER, such as xeroderma pigmentosum complimentation group A (XPA). Microarray and reverse transcription-PCR data indicate a 2.6-fold decrease in intracellular XPA mRNA in transgenic MCF-7 cells overexpressing HMGA1 proteins compared with non-HMGA1-expressing cells. XPA protein levels are also approximately 3-fold lower in HMGA1-expressing MCF-7 cells. Moreover, whereas a >2-fold induction of XPA proteins is observed in normal MCF-7 cells 30 min after UV exposure, no apparent induction of XPA protein is observed in MCF-7 cells expressing HMGA1. Mechanistically, we present both chromatin immunoprecipitation and promoter site-specific mutagenesis evidence linking HMGA1 to repression of XPA transcription via binding to a negative regulatory element in the endogenous XPA gene promoter. Phenotypically, HMGA1-expressing cells exhibit compromised removal of cyclobutane pyrimidine dimer lesions, a characteristic of cells that express low levels of XPA. Importantly, we show that restoring expression of wild-type XPA in HMGA1-expressing cells rescues UV resistance comparable with that of normal MCF-7 cells. Together, these data provide strong experimental evidence that HMGA1 proteins are involved in inhibiting XPA expression, resulting in increased UV sensitivity in cells that overexpress these proteins. Because HMGA1 proteins are overexpressed in most naturally occurring cancers, with increasing cellular concentrations correlating with increasing metastatic potential and poor patient prognosis, the current findings provide new insights into previously unsuspected mechanisms contributing to tumor progression.
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http://dx.doi.org/10.1158/0008-5472.CAN-06-1689DOI Listing
July 2007