Kinase target expression

In contrast to c-Jun, phosphorylation of the tumor suppressor p53 by CSN-associated kinases targets the protein for degradation by the Ub system [35]. For p53 stability, modification on Thrl55 is most important as shown by mutational analysis [35] and by using different p53 peptides [31]. Mutation of Thrl55 to Val led to stabilization of the transiently expressed p53 mutant in HeLa as well as in HL60 cells [35]. Inhibitors of CSN-associated kinases such as curcumin [18] caused stabilization of cellular p53 followed by massive cell death [35]. 

Recently, a series of lentivirus vectors were developed for transduction of hepa-tocytes in vivo (78). Various promoters, such as the human CMV, the human phos-phoglycerate kinase (PGK) and the mouse albumin promoter, were introduced into the FlIV-1-based vector. These vectors showed enhanced nuclear translocation in hepatocytes and improved transgene expression. Interestingly, targeted expression to the liver could be accomplished by the use of the albumin promoter. Therapeutic levels of human factor IX were achieved after a single injection. 

M. W. R. Robertson, M. Wang, G. P. Siegal, M. Rosenfeld, R. S. N. Ashford, R. D. Alvarez, R. I. Garver, and D. T. Curiel, Use of a tissue-specific promoter for targeted expression of the herpes simplex virus thymidine kinase gene in cervical carcinoma cells, Cancer Gene Ther. 5 331 (1998). 

Kerkhoff E, Fedorov LM, Siefken R, Walter AO, Papadopoulos T, Rapp UR. Lung-targeted expression of the c-Raf-1 kinase in transgenic mice exposes a novel oncogenic character of the wild-type protein. Cell Growth Differ 2000 11 185-190. 

BDNF (brain-derived neurotrophic factor) is a neuro-trophin, i.e. a target-derived growth factor, which is expressed in the brain predominantly in the hippocampus. It acts through its tyrosine kinase receptor, trkB,... 

A subfamily of Rho proteins, the Rnd family of small GTPases, are always GTP-bound and seem to be regulated by expression and localization rather than by nucleotide exchange and hydrolysis. Many Rho GTPase effectors have been identified, including protein and lipid kinases, phospholipase D and numerous adaptor proteins. One of the best characterized effector of RhoA is Rho kinase, which phosphorylates and inactivates myosin phosphatase thereby RhoA causes activation of actomyosin complexes. Rho proteins are preferred targets of bacterial protein toxins ( bacterial toxins). 

Note that application in the particular indications is usually restricted either to patients expressing the target (e.g. trastuzumab, cetuximab, lapatinib, imatinib) and/or after failure of prior therapies (e.g. cetuximab, erlotinib, lapatinib, sutinib, dasatinib). Furthermore, for cancer treatment most tyrosine kinase inhibitors are applied in combination with conventional chemotherapeutic drugs, such as fluorouracil, taxanes, platin-based regimens, anthracylines and irinotecan or radiotherapy. 

---