Although an effective chemotherapeutic strategy, CY treatment is associated with multiple side effects, particularly urinary bladder hemorrhagic cystitis (Cox, 1979; Bon et al., 2003; Morandi et al., 2005). The Vorinostat HDAC1 high urotoxicity of CY has been linked to the generation of acrolein (Cox, 1979); hence we examined whether GSTP, which catalyzes the conjugation of acrolein with glutathione (Berhane et al., 1994), prevents CY toxicity by promoting acrolein metabolism. To test the role of GSTP, we used GSTP-null mice. Because mouse GSTP genes are orthologous to human GSTP1, sharing 85% sequence identity at the genetic level (Board, 2007), deletion of GSTP genes in mice represents a true null genetic model of human GSTP1 deficiency. The GSTP-null mice develop, grow, and reproduce normally and have normal urinary bladder histology as in WT mice.
There are no obvious anatomical or physiological defects caused by GSTP deletion; however, it is known that the GSTP-null mice are more sensitive to TPA-induced skin tumorigenesis (Henderson et al., 1998), as well as cigarette smoke- and acrolein-induced endothelial dysfunction (Conklin et al., 2009). In contrast, GSTP-null mice are more resistant to acetaminophen-induced hepatotoxicity (Henderson et al., 2000), indicating the need to assess the effects of GSTP deletion on the sensitivity of a specific target tissue. Our results show that deletion of GSTP does not affect overall CY metabolism or systemic CY toxicity. We found no difference in the CY metabolism in WT and GSTP-null mice hepatic microsome
The Wnt signalling pathway is composed of canonical and non-canonical signals.
The canonical Wnt signalling pathway that regulates cell fate and proliferation is initiated by binding of Wnt ligands to frizzled transmembrane receptors, and low-density lipoprotein receptor-related proteins. ��-Catenin associates with T-cell factor (Tcf)/lymphocyte enhancer transcription factors to activate target genes that are related to cell survival, proliferation and invasion (Moon et al, 2004; Clevers, 2006). The non-canonical Wnt signalling pathway consists of Wnt/Ca2+ pathway and Wnt/c-Jun N-terminal kinase (JNK) (planar cell polarity) pathway (Cohen et al, 2008). In the Wnt/Ca2+ pathway, Wnt activates intracellular Ca2+ signalling, as well as Ca2+-dependent protein kinases, such as protein kinase C (PKC) and calmodulin-dependent protein kinase II.
In the Wnt/JNK pathway, receptor stimulation activates Dishevelled (Dvl), which in turn activates Rho family of GTPases such as RhoA and Rac. RhoA stimulates c-Jun expression through phosphorylation of c-Jun by Rho-associated kinase (ROCK) (Marinissen et al, 2004). Accumulating evidence suggests that non-canonical Wnt signalling is important in regulating cell polarity and movement Batimastat (Veeman et al, 2003).