Reflections

  Significance Overview   RET/PTCs are a group of oncogenic fusion proteins derived from the proto-oncogene c-RET, structurally related to a family of receptor tyrosine kinases (1-3). RET/PTCs result from joining the carboxy-terminus of fusion partners with the amino-terminus of c-RET, leading to constitutively active kinase. Of the 11 different fusion genes reported, RET/PTC1 or RP1 and RET/PTC3 or RP3 are the most prevalent (1). In the case of RP3, the amino terminus is derived from the androgen receptor-associated protein, ARA-70 (Fig. 1) (4). RP3 drives three different pathways that strongly influence biological properties of the tumor. First, the constitutively active c-terminal RET kinase domain activates RAS/BRAF/MEK/ERK, PI3K/AKT, p38MAPK, and JNK pathways leading to thyrocyte transformation (5). Second, kinase activity leads to precocious phosphorylation of RP3 itself and other intracellular proteins that provide tumor-specific targets for the adaptive immu...

  Specific aims Mechanistic target for rapamycin (mTOR) has recently emerged as central regulator of cell metabolism with key role in cell proliferation and cancer development.  Our investigation of human follicular thyroid cancer (FTC) tissue samples demonstrated activation of mTOR along with p-CREB. Our transgenic mouse model of human FTC by protein kinase A (PKA) activation (due to knockdown of the regulatory subunit PRKAR1A gene implicated as tumor suppressor in human FTC), faithfully replicated the human FTC results with activation of mTOR and p-CREB. Examination of signaling pathways in our mouse model, we interestingly found activation of AMPK (Thr-172) which is not only an energy sensor but also termed as negative regulator of mTOR pathway. However, AMPK is also essential to prevent cellular apoptosis in cells subjected to various kinds of stress. We therefore hypothesize that activation of both AMPK and mTOR pathways are essential, balancing the cellular metabolic pat...

Warburg's effect is quoted many times to describe the faulty metabolic pathways in tumor cells. Tumor cells which are rapidly dividing are known to create a hypoxic microenvironment which does not support glucose oxidation. Under these circumstances, glycolysis becomes a dominant metabolic pathway to generate energy for the rapidly dividing tumor cells. However, this may not be the complete story. In recent years, there has been a tremendous amount of work being done to explore the metabolic pathways involved in various tumors. All this now depicts a newer reality where glycolysis instead of being "The pathway" is now thought to be one of the pathways used by the tumor cells. Of interest are the protein metabolic pathways such as glutamine and proline pathways, The nucleic acid metabolic pathways and my present interest, the fatty acids pathways.  If we consider that alternative pathways such as fatty acid oxidation, protein metabolic pathways,  then all the proteins ...