Post on 23-Jan-2016
description
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
A model summarizing the major mechanisms involved in Cd carcinogenesis
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
Some of the genes induced by cadmium
Translational Genes
Translation initiation factor 3Translation elongation factor 1δ
Transcription Factors
MTF1USFNFκBNrf2
FAS-initiated apoptotic cascade
Proposed pathways for ROS in Cd toxicology and carcinogenesis following acute and chronic exposures
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
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
Chromium uptake, intracellular chemistry and damage
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
Pathways leading to observation of single-strand DNA breaks (SSB) and double-strand DNA breaks (DSB)