HMGA1 Mediates the Activation of the CRYAB Promoter by BRG1

Duncan, Beverly; Zhao, Keji

doi:10.1089/dna.2007.0629

Cited by 19 publications

(17 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, among the most significant biological changes induced by HMGA1 overexpression are (i) alterations in the transcription of a subset of cancer-related target genes whose promoters are directly regulated by the HMGA1 protein (3,28,40,59,113,116) and (ii) the activation of signal transduction pathways that can lead to anomalous downstream gene activation/repression and cancer (29,100,115,117,124).…”

Section: Discussionmentioning

confidence: 99%

HMGA1 Levels Influence Mitochondrial Function and Mitochondrial DNA Repair Efficiency

Mao

Wertzler

Maloney

et al. 2009

Molecular and Cellular Biology

View full text Add to dashboard Cite

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.Aberrant alterations in mitochondrial function are observed in a wide range of human conditions and diseases (10, 109), including cancer (19,22,51). Because of their prevalence, mitochondrial abnormalities in cancer cells have been extensively investigated (17,39,84,118). Even in the presence of an adequate oxygen supply, the mitochondria of cancer cells are almost universally deficient in their ability to generate ATP via oxidative phosphorylation and therefore rely heavily on glycolytic metabolism for energy production (the so-called Warburg effect) (119, 120). Likewise, cancer cells often exhibit electron transport chain deficiencies (90), generate smaller amounts of ATP and higher levels of reactive oxygen species (ROS) than normal cells (45, 65), display calcium signaling defects (101), and frequently exhibit alterations in their mitochondrial transmembrane potential (56, 57). Many cancers also exhibit reductions in both mitochondrial mass and mitochondrial DNA (mtDNA) levels (31,80,118,125,128), as well as significantly altered levels of mtDNA transcription (36,50,55,66). It is also well documented that mtDNA in cancer cells is more susceptible to somatic mutation than nuclear DNA (nDNA) (8,12,22,93,104), partially as a consequence of the limited repair capabilities of mitochondria compared to the mechanisms responsible for the repair of nDNA (12,13,39,76).The underlying molecular causes for mitochondrial dysfunction in most cancers are unknown, although available evidence suggests that there are many possible contributing factors that interact with ...

show abstract

Section: Discussionmentioning

confidence: 99%

HMGA1 Levels Influence Mitochondrial Function and Mitochondrial DNA Repair Efficiency

Mao

Wertzler

Maloney

et al. 2009

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…HMGA1 induces expression of the CRYAB gene, which encodes the αβ-Crystallin (CRYAB) protein, a heat-shock protein that is highly expressed in the ocular lens of vertebrates [261]. Deficiencies in CRYAB and other crystalline proteins are associated with cataracts.…”

Section: Hmga1 Transcriptional Targetsmentioning

confidence: 99%

The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development

Sumter¹,

Xian²,

Huso³

et al. 2016

CMM

103

View full text Add to dashboard Cite

Background & Objectives Chromatin structure is the single most important feature that distinguishes a cancer cell from a normal cell histologically. Chromatin remodeling proteins regulate chromatin structure and high mobility group A (HMGA1) proteins are among the most abundant, nonhistone chromatin remodeling proteins found in cancer cells. These proteins include HMGA1a/HMGA1b isoforms, which result from alternatively spliced mRNA. The HMGA1 gene is overexpressed in cancer and high levels portend a poor prognosis in diverse tumors. HMGA1 is also highly expressed during embryogenesis and postnatally in adult stem cells. Overexpression of HMGA1 drives neoplastic transformation in cultured cells, while inhibiting HMGA1 blocks oncogenic and cancer stem cell properties. Hmga1 transgenic mice succumb to aggressive tumors, demonstrating that dysregulated expression of HMGA1 causes cancer in vivo. HMGA1 is also required for reprogramming somatic cells into induced pluripotent stem cells. HMGA1 proteins function as ancillary transcription factors that bend chromatin and recruit other transcription factors to DNA. They induce oncogenic transformation by activating or repressing specific genes involved in this process and an HMGA1 “transcriptome” is emerging. Although prior studies reveal potent oncogenic properties of HMGA1, we are only beginning to understand the molecular mechanisms through which HMGA1 functions. In this review, we summarize the list of putative downstream transcriptional targets regulated by HMGA1. We also briefly discuss studies linking HMGA1 to Alzheimer’s disease and type-2 diabetes. Conclusion Further elucidation of HMGA1 function should lead to novel therapeutic strategies for cancer and possibly for other diseases associated with aberrant HMGA1 expression.

show abstract

“…Transcriptional activation of CRYAB has been demonstrated to depend on either BRG-1 containing, or hBRM-associated factor (BAF) containing, SWI/SNF chromatin remodeling complexes [90]. Recently Zhao and his colleagues identified a 30 bp DNA element in the gene’s promoter situated between −90 to −60 bp immediately upstream from the start site that is responsible for BRG-1 mediated activation of CRYAB transcription and whose action is chromatin dependent [44]. Point mutagenesis studies demonstrated that this BRG-1 response element contains an A/T-rich site for HMGA binding and a consensus recognition site for the AP-1 transcription factor.…”

Section: Hmga Proteins and Localized Nucleosome Structurementioning

confidence: 99%

Nuclear functions of the HMG proteins

Reeves

2010

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

222

224

View full text Add to dashboard Cite

I. Summary Although the three families of mammalian HMG proteins (HMGA, HMGB and HMGN) participate in many of the same nuclear processes, each family plays its own unique role in modulating chromatin structure and regulating genomic function. This review focuses on the similarities and differences in the mechanisms by which the different HMG families impact chromatin structure and influence cellular phenotype. The biological implications of having three architectural transcription factor families with complementary, but partially overlapping, nuclear functions are discussed.

show abstract

HMGA1 Mediates the Activation of the CRYAB Promoter by BRG1

Cited by 19 publications

References 37 publications

HMGA1 Levels Influence Mitochondrial Function and Mitochondrial DNA Repair Efficiency

HMGA1 Levels Influence Mitochondrial Function and Mitochondrial DNA Repair Efficiency

The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development

Nuclear functions of the HMG proteins

Contact Info

Product

Resources

About