carcinogenic metals
DESCRIPTION
Carcinogenic Metals. International Agency for Research on Cancer (IARC) classification. Group 1: Confirmed human carcinogens As, Be, Cd, Cr(VI), Ni Group 2B: Possibly carcinogenic to humans Co. A model summarizing the major mechanisms involved in Cd carcinogenesis. - PowerPoint PPT PresentationTRANSCRIPT
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Carcinogenic Metals
International Agency for Research on Cancer (IARC) classification
Group 1: Confirmed human carcinogensAs, Be, Cd, Cr(VI), Ni
Group 2B: Possibly carcinogenic to humansCo
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A model summarizing the major mechanisms involved in Cd carcinogenesis
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Categories of Genes Induced by Cd
1. Immediate early response genes (IEGs)
2. Stress response genes
3. Transcription factors
4. Translation factors
5. Miscellaneous genes
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Some of the genes induced by cadmium
Translational Genes
Translation initiation factor 3Translation elongation factor 1δ
Transcription Factors
MTF1USFNFκBNrf2
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FAS-initiated apoptotic cascade
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Proposed pathways for ROS in Cd toxicology and carcinogenesis following acute and chronic exposures
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Structure of residues 19 – 44 of β-Catenin phosphorylated on Ser 33 and 37
Oncogenic mutations in codon 33:
TCT → TAT Ser → TyrTCT → TTT Ser → Phe
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The α-cadherin/β-Catenin complex connects to the actin via α-Catenin and some actin-binding proteins, forming a rigid cytoskeleton. When cells are exposed to Wnt signal, cell surface receptors are activated and block β-Catenin phosphorylation and its subsequent ubiquitination. β-Catenin is thus diverted from the proteasome, and it accumulates and enters the nucleus, where it finds a partner of the TCF/LEF family. Together, they activate new gene expression programs.
Role of β-catenin in Wnt signaling pathway
Proteasome: protein complex that degrades tagged proteins
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Chromium uptake, intracellular chemistry and damage
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Chromium-DNA Adducts
BO
O
OPO
O
O
BO
OP-O
O
O
Cr
L
L
LL
L
NH
N
N
O
NH2N
O
O
OP
O O
O
Cr
L
L L
L
BO
O
OPO
O
O
BO
OP-O
O
O
CrOH2
OH
Binary Adducts
phosphotriester (non mutagenic) intramolecular cross link (mutagenic)
Ternary Adducts
Cys adduct (mutagenic)
O
S
NH2
O
BO
O
OPO
O
O
BO
OP-O
O
O
Cr
OH2
OH2
ascorbate adduct (mutagenic)
O
OH
O
O
OH
HOH2O
HO
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Pathways leading to observation of single-strand DNA breaks (SSB) and double-strand DNA breaks (DSB)
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