Dr. Bansidhar Datta: "Suppression of Tumor Growth Via Gene Transfer"
My research focus is to suppress tumor growth in ex-vivo cell culture model and in vivo animal model by regulating the expression of p67 gene. P67, also known as MetAP2, regulates the level of phosphorylation of eukaryotic initiation factor 2 (eIF2) and extracellular signal-regulated kinases 1 and 2 (ERK1/2). EIF2 maintains the rate of global protein synthesis, whereas ERK1/2 controls the cell signaling mediated by the proto-oncogene Ras. In more than 60% of human cancers, Ras is mutated. Expression of mutant Ras in ex-vivo cell culture system transforms cells and injection of these transformed cells into nude mice causes localized tumor formation. However, this tumor growth could be suppressed by overexpressing p67 prior to the injection into nude mice. Well-developed blood vessels were identified in mouse tumors caused due to the expression of mutant Ras whereas, undeveloped and spongy type of blood vessels were more prominent in tumors if p67 was overexpressed in Ras-transformed cells prior to the injection into nude mice. These observations also indicate that p67 is interfering in angiogenesis in tumors.
Expression of p67 could be controlled via several mechanisms: (i) when cells were treated with fumagillin, an epoxy compound isolated from fungus, that binds to H231 of p67 covalently and inhibits it auto-proteolytic activity. As a result, p67 accumulates inside the cells and binds to ERK1/2 to inhibit their phosphorylation. This also leads to the dissociation of p67 from EIF2, allowing it to be phosphorylated by its inhibitory kinases and shuts down the global protein synthesis. The inhibition of ERK1/2 phosphorylation by p67 leads to the inhibition of cell signaling mediated by Ras and thus acts as a negative regulator of cell cycle. Together, p67 acts as a mediator communicating with cell cycle and protein synthesis machinery. (ii) The promoter regions of p67 contains several cis-elements that could act as binding sites for different activators, which can control the expression of p67 in response to several growth conditions. (iii) Overexpression of cloned p67 gene in mammalian cells via different expression vectors. Using these different mechanisms we are now focusing on the suppression of cell growth of different human tumor cells.
Scholarly, Creative & Professional Activities
- Datta, B. (2014) Diversified roles of p67/MetAP2 as a regulator of cell growth and differentiation, in tumor suppression, and in obesity (Review). Curr. Topics Biochem. Res. 16:41-52.
- Datta, B., Datta, R., and Tammali, R. (2014) Lysine-rich domains of eukaryotic initiation factor 2-associated glycoprotein, p67 are involved in the suppression of phosphorylation of several cellular kinases. Intl. J. of Biotech. Biochem. 10:141-156.
- Tammali, R., Datta, R., Datta, B. (2014) Phosphorylation of double-stranded RNA activated kinase, PKR is induced by eukaryotic initiation factor 5 (eIF5), which is also a major substrate for this kinase in vitro. Intl. J. of Biotech. Biochem. 10:127-140.
- Datta, B. and Datta, R. (2014) Inhibition of phosphorylation of cdk2 and cdc2 in rat tumor hepatoma cells constitutively expressing specific p67 mutants. Intl. J. of Biotech. Biochem. 10:113-125.
- Datta, B. and Datta, R. (2014) Phosphorylation of eukaryotic initiation factor 2a during differentiation of mouse myoblasts into myotubes is mediated by an unknown kinase. Intl. J. Adv. Res. Chem. Sci. 1:1-5.
- Ghosh,A., Tammali, R., Balusu, R., Datta, R., Chattopadhyay, A., Bhattacharya, M., and Datta, B. (2014) Oligomerization of the eukaryotic initiation factor 2-associated glycoprotein p67 requires N-terminal 1-107 amino acid residues. Intl. J. Appl. Biotech. Biochem. 4:25-44.
- Datta, B., Earl, D., Roods, M., Datta, S. (2014) Analysis of p67/MetAP2 gene from mammals. Intl. J. Mol. Genet. 5:1-12.
- Majumdar, A., Ghosh, A., Datta, S., Prudner, B., and Datta, B. (2010) P67/MetAP2 suppresses K-RasV12 mediated transformation of NIH3T3 mouse fibroblasts in culture and in athymic mice. Biochemistry 49:10146-10157.
- Datta, B., (2009) Roles of P67/MetAP2 as a tumor suppressor – a review. BBA - Reviews on Cancer. 1796:281-292.
- Datta, B., Ghosh, A., Majumdar, A. & Datta, R. (2007) Autoproteolysis of Rat p67 Generates Several Peptide Fragments: The N-Terminal Fragment, p26, Is Required for the Protection of eIF2a from Phosphorylation. Biochemistry 46:3465-3475.
- Ghosh, A., Datta, R., Majumdar, A., Bhattacharya, M., and Datta, B. (2006) The N-terminal lysine residue-rich domain II and the 340-430 amino acid segment of eukaryotic initiation factor 2-associated glycoprotein p67 are the binding sites for the g-subunit of eIF2. Exp. Cell Res. 312:3184-3203.
- Datta, B., Datta, R., Ghosh, A., and Majumdar, A. (2006) The binding between p67 and eukaryotic initiation factor 2 plays important roles in the protection of eIF2alpha from phosphorylation by kinases. Arch. Biochem. Biophys. 452:138-148.