Calcium-independent effects of cadmium on actin assembly in mesangial and vascular smooth muscle cells

Wang, Zheng; Chin, Tracy A.; Templeton, Douglas M.

doi:10.1002/(sici)1097-0169(1996)33:3<208::aid-cm5>3.0.co;2-6

Cited by 49 publications

(21 citation statements)

References 51 publications

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“…Cd causes disruption of cytoskeletal components, including actin, in several cell types [24,25]. Cell motility is regulated by the assembly and disassembly of the F-actin cytoskeleton, while F-actin also generates contractile forces to maintain the structure of intercellular contacts [26,27,28].…”

Section: Resultsmentioning

confidence: 99%

Low Dose Cadmium Inhibits Proliferation of Human Renal Mesangial Cells via Activation of the JNK Pathway

Chen

Cheng

et al. 2016

IJERPH

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Cadmium (Cd) is a heavy metal and environmental pollutant. The kidney is the principal target organ of Cd exposure. Previously, we found that low concentration of Cd damages the integrity of the glomerular filtration barrier. However, little is known about the effects of Cd on renal mesangial cells, which provide structural support for the glomerular capillary loops and regulate intraglomerular blood flow. In this study, human renal mesangial cells (HRMCs) were cultured in the presence of serum and treated with 4 μM Cd. We found that Cd activates the c-Jun N-terminal kinase (JNK) pathway, and increases the protein levels of c-Jun and c-Fos. Cd treatment also induces a decrease in proliferation and an increase in apoptosis of HRMCs, but only the decrease in HRMC proliferation was reversed by pretreatment with SP600125, an inhibitor of the JNK pathway. In addition, Cd does not change the expression of α-smooth muscle actin and platelet-derived growth factor receptor-β, the markers of mesangial cells, or the alignment of the filamentous actin (F-actin) cytoskeleton of HRMCs. Our data indicate that the JNK pathway mediates the inhibitory effects of Cd on HRMC proliferation.

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Section: Resultsmentioning

confidence: 99%

Low Dose Cadmium Inhibits Proliferation of Human Renal Mesangial Cells via Activation of the JNK Pathway

Chen

Cheng

et al. 2016

IJERPH

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“…Cadmium is also reported to be a spindle poison, al-though the block in G 2 /M is, at best, only partial (45,80,81). Nevertheless, in cells overexpressing PLU-1/JARID1B, the small increase in the number of cells in G 2 /M after cadmium treatment was consistently reduced.…”

Section: Discussionmentioning

confidence: 99%

Functional Analysis of the Transcription Repressor PLU-1/JARID1B

Scibetta

Santangelo

Coleman

et al. 2007

Molecular and Cellular Biology

120

119

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The PLU-1/JARID1B nuclear protein, which is upregulated in breast cancers, belongs to the ARID family of DNA binding proteins and has strong transcriptional repression activity. To identify the target genes regulated by PLU-1/JARID1B, we overexpressed or silenced the human PLU-1/JARID1B gene in human mammary epithelial cells by using adenovirus and RNA interference systems, respectively, and then applied microarray analysis to identify candidate genes. A total of 100 genes showed inversely correlated differential expression in the two systems. Most of the candidate genes were downregulated by the overexpression of PLU-1/JARID1B, including the MT genes, the tumor suppressor gene BRCA1, and genes involved in the regulation of the M phase of the mitotic cell cycle. Chromatin immunoprecipitation assays confirmed that the metallothionein 1H (MT1H), -1F, and -1X genes are direct transcriptional targets of PLU-1/JARID1B in vivo. Furthermore, the level of trimethyl H3K4 of the MT1H promoter was increased following silencing of PLU-1/JARID1B. Both the PLU-1/JARID1B protein and the ARID domain selectively bound CG-rich DNA. The GCACA/C motif, which is abundant in metallothionein promoters, was identified as a consensus binding sequence of the PLU-1/ JARID1B ARID domain. As expected from the microarray data, cells overexpressing PLU-1/JARID1B have an impaired G 2 /M checkpoint. Our study provides insight into the molecular function of the breast cancerassociated transcriptional repressor PLU-1/JARID1B.The PLU-1 nuclear protein is expressed in most primary breast cancers and breast cancer cell lines (4, 46), while its expression in normal adult tissues is largely restricted to testes (46), where it is expressed in spermatogonia and in specific stages of meiosis (48). However, significant expression is also seen in the murine pregnant mammary gland (4) and in the embryonic mammary bud (4, 47). Thus, in addition to being elevated in breast cancer, PLU-1 is involved in the development and differentiation of the mammary gland.The PLU-1 gene encodes a 1,544-amino-acid multidomain protein that is exclusively localized to the nucleus. Sequence homology analysis shows that it contains several conserved domains, including the ARID DNA binding domain (AT-richinteracting domain), plant homeodomain/leukemia-associated protein domains (PHD domains), Jumonji domains, and putative nuclear localization signals (46). The ARID domain, the N-terminal and C-terminal Jumonji domains (JmJN and JmJC), two of the plant homeodomain domains, and a novel Trp/Tyr/Phe/Cys domain (the PLU domain), which overlaps the JmJC domain (62), are conserved in the four members of the JARID1 subfamily of the larger family of ARID proteins (15 proteins to date) (86). Although their sequence homology is high, these proteins appear to have diverse functions, with JARID1A (RBP2) being involved in activating transcription from nuclear receptors (14), PLU-1 (now referred to as PLU-1/JARID1B) being a strong transcriptional repressor (75, 88), and JARID1C (the SMCX gene) ...

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“…Although literature on the cellular action of Cd is available, the precise mechanisms by which Cd induces cell damage remain obscure. Cd has pleiotropic effects including the induction of metallothioneins, heat shock proteins (6,8) and protooncogenes (60), interference with calcium/calmodulin signaling (8), profound rearrangements of microfilaments (59), and stimulation of signal transduction cascades involving the MAP kinases (MAPK) Erk1/2 (12,54,60), JNK (12), and p38 (29,54).…”

mentioning

confidence: 99%

p38 MAPK/HSP25 signaling mediates cadmium-induced contraction of mesangial cells and renal glomeruli

Hirano

Sun

DeGuzman

et al. 2005

American Journal of Physiology-Renal Physiology

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The environmental pollutant cadmium affects human health, with the kidney being a primary target. In addition to proximal tubules, glomeruli and their contractile mesangial cells have also been identified as targets of cadmium nephrotoxicity. Glomerular contraction is thought to contribute to reduced glomerular filtration, a characteristic of cadmium nephrotoxicity. Because p38 MAPK/HSP25 signaling has been implicated in smooth muscle contraction, we examined its role in cadmium-induced contraction of mesangial cells. We report that exposure of mesangial cells to cadmium resulted in 1) cell contraction, 2) activation of MAP kinases, 3) increased HSP25 phosphorylation coincident with p38 MAP kinase activation, 4) sequential phosphorylation of the two phosphorylation sites of mouse HSP25 with Ser15 being phosphorylated before Ser86, 5) reduction of oligomeric size of HSP25, and 6) association of HSP25 with microfilaments. Exposure of isolated rat glomeruli to cadmium also resulted in contraction and increased HSP25 phosphorylation. The cadmium-induced responses were inhibited by the specific p38 MAP kinase inhibitor SB-203580, and cadmium-induced phosphorylation of HSP25 was inhibited by expression of a dominant-negative p38 MAP kinase mutant. These findings tentatively suggest that cadmium-induced nephrotoxicity results, in part, from glomerular contraction due to p38 MAP kinase/ HSP25 signaling-dependent contraction of mesangial cells. With regard to the cellular action of HSP25, these data support a change in paradigm: in addition to its well-established cytoprotective function,

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Calcium-independent effects of cadmium on actin assembly in mesangial and vascular smooth muscle cells

Cited by 49 publications

References 51 publications

Low Dose Cadmium Inhibits Proliferation of Human Renal Mesangial Cells via Activation of the JNK Pathway

Low Dose Cadmium Inhibits Proliferation of Human Renal Mesangial Cells via Activation of the JNK Pathway

Functional Analysis of the Transcription Repressor PLU-1/JARID1B

p38 MAPK/HSP25 signaling mediates cadmium-induced contraction of mesangial cells and renal glomeruli

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