Rabbit Anti-Human PTK6 Polyclonal antibody

The common R653Q variant (approximate to 20% homozygosity in Caucasians) in the synthetase domain of the folate-metabolizing enzyme MTHFD1 reduces purine synthesis. Although this variant does not appear to affect risk for colorectal cancer, we questioned whether it would affect growth of colorectal tumors. We induced tumor formation in a mouse model for MTHFD1-synthetase deficiency (Mthfd1S(+/-)) using combined administration of azoxymethane (AOM) and dextran sodium sulfate (DSS) in male and female wild-type and Mthfd1S(+/-) mice. Tumor size was significantly smaller in MthfdS(+/-) mice, particularly in males. A reduction in the proliferation of MthfdS(+/-) mouse embryonic fibroblast cell lines, compared with wild-type lines, was also observed. Tumor number was not influenced by genotype. The amount of inflammation observed within tumors from male Mthfd1S(+/-) mice was lower than that in wild-type mice. Gene expression analysis in tumor adjacent normal (pre-neoplastic) tissue identified several genes involved in proliferation (Fosb, Fos, Ptk6, Esr2, Atf3) and inflammation (Atf3, Saa1, TNF-) that were downregulated in MthfdS(+/-) males. In females, MthfdS(+/-) genotype was not associated with these gene expression changes, or with differences in tumor inflammation. These findings suggest that the mechanisms directing tumor growth differ significantly between males and females. We suggest that restriction of purine synthesis, reduced expression of genes involved in proliferation, and/or reduced inflammation lead to slower tumor growth in MTHFD1-synthetase deficiency. These findings may have implications for CRC tumor growth and prognosis in individuals with the R653Q variant. (c) 2016 Wiley Periodicals, Inc.

Akt kinase, a member of AGC kinases, is important in many cellular functions including proliferation, migration, cell growth and metabolism. There are three known Akt isoforms which play critical and diverse roles in the cardiovascular system. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. Beta-catenin/Tcf-4, Gal and Stat-3 are some of few known transcriptional regulators of AICT gene. Threonine 308 and serine 473 are the two critical phosphorylation sites of Akt1. Translocation of Akt to the cell membrane facilitates PDK1 phosphorylation of the threonine site. The serine site is phosphorylated by mTORC2. Ack1, Src, PTK6, TBK1, IKBKE and IKK epsilon are some of the non-canonical pathways which affect the Ala activity. Protein-protein interactions of Akt to actin and Hsp90 increase the Akt activity while Akt binding to other proteins such as CTMP and TRB3 reduces the Akt activity. The action of Akt on its downstream targets determines its function in cardiovascular processes such as cell survival, growth, proliferation, angiogenesis, vasorelaxation, and cell metabolism. Akt promotes cell survival via caspase-9, YAP, Bcl-2, and Bcl-x activities. Inhibition of Fox() proteins by Akt also increases cell survival by transcriptional mechanisms. Akt stimulates cell growth and proliferation through mTORC1. Akt also increases VEGF secretion and mediates eNOS phosphoiyladon, vasorelaxation and angiogenesis. Akt can increase cellular metabolism through its downstream targets GSK3 and GLUT4. The alterations of Akt signaling play an important role in many cardiovascular pathological processes such as atherosclerosis, cardiac hypertrophy, and vascular remodeling. Several Akt inhibitors have been developed and tested as anti-tumor agents. They could be potential novel therapeutics for the cardiovascular diseases. Published by Elsevier Inc.