Editing Arsenic poisoning (section)

===Heat shock response===
Another aspect is the similarity of arsenic effects to the heat shock response. Short-term arsenic exposure has effects on signal transduction inducing heat shock proteins with masses of 27, 60, 70, 72, 90, and 110 kDa as well as [[metallothionein]], [[ubiquitin]], mitogen-activated [MAP] kinases, [[Extracellular signal-regulated kinases|extracellular regulated kinase]] [ERK], c-jun terminal kinases [JNK] and p38.<ref name=Bernstam2000/><ref name=DelRazo2001>{{cite journal|vauthors=Del Razo LM, Quintanilla-Vega B, Brambila-Colombres E, Calderón-Aranda ES, Manno M, Albores A |title=Stress proteins induced by arsenic |journal=Toxicology and Applied Pharmacology |volume=177 |issue=2 |pages=132–48 |date=December 2001 |pmid=11740912 |doi=10.1006/taap.2001.9291|bibcode=2001ToxAP.177..132D }}</ref>
Via JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines.<ref name=Bernstam2000/><ref name=Cavigelli1996>{{cite journal|vauthors=Cavigelli M, Li WW, Lin A, Su B, Yoshioka K, Karin M |title=The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase |journal=The EMBO Journal |volume=15 |issue=22 |pages=6269–79 |date=November 1996 |pmid=8947050 |pmc=452450|doi=10.1002/j.1460-2075.1996.tb01017.x }}</ref><ref name=Ludwig1998>{{cite journal|vauthors=Ludwig S, Hoffmeyer A, Goebeler M |title=The stress inducer arsenite activates mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 via a MAPK kinase 6/p38-dependent pathway |journal=The Journal of Biological Chemistry |volume=273 |issue=4 |pages=1917–22 |date=January 1998 |pmid=9442025 |doi=10.1074/jbc.273.4.1917|display-authors=etal|doi-access=free }}</ref> The effects are largely dependent on the dosing regime and may be as well inversed.

As shown by some experiments reviewed by Del Razo (2001), reactive oxygen species induced by low levels of inorganic arsenic increase the transcription and the activity of the activator protein 1 (AP-1) and the nuclear factor-κB ([[NF-κB]]) (maybe enhanced by elevated MAPK levels), which results in c-fos/c-jun activation, over-secretion of pro-inflammatory and growth promoting cytokines stimulating cell proliferation.<ref name=DelRazo2001/><ref name=Simeonova2000>{{cite journal|vauthors=Simeonova PP, Luster MI |title=Mechanisms of arsenic carcinogenicity: genetic or epigenetic mechanisms? |journal=Journal of Environmental Pathology, Toxicology and Oncology |volume=19 |issue=3 |pages=281–6 |year=2000 |pmid=10983894}}</ref> Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water.<ref>{{cite journal|vauthors=Germolec DR, Yoshida T, Gaido K |title=Arsenic induces overexpression of growth factors in human keratinocytes |journal=Toxicology and Applied Pharmacology |volume=141 |issue=1 |pages=308–18 |date=November 1996 |pmid=8917704 |doi=10.1006/taap.1996.0288|display-authors=etal}}</ref>

Increased AP-1 and NF-κB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels.<ref name=Hamadeh1999>{{cite journal|vauthors=Hamadeh HK, Vargas M, Lee E, Menzel DB |title=Arsenic disrupts cellular levels of p53 and mdm2: a potential mechanism of carcinogenesis |journal=Biochemical and Biophysical Research Communications |volume=263 |issue=2 |pages=446–9 |date=September 1999 |pmid=10491313 |doi=10.1006/bbrc.1999.1395}}</ref> Thus, taking into account p53's function, a lack of it could cause a faster accumulation of mutations contributing to carcinogenesis. However, high levels of inorganic arsenic inhibit NF-κB activation and cell proliferation. An experiment of Hu et al. (2002) demonstrated increased binding activity of AP-1 and NF-κB after acute (24 h) exposure to +3 sodium arsenite, whereas long-term exposure (10–12 weeks) yielded the opposite result.<ref name=hu2002/> The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis.<ref name=hu2002/> As the contradicting findings and connected mechanistic hypotheses indicate, there is a difference in acute and chronic effects of arsenic on signal transduction which is not clearly understood yet.{{Citation needed|date=November 2009}}