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...

  Targeting AMPK and mTOR pathways in Atopic Dermatitis Rationale Eczema or atopic dermatitis is chronic inflammation of the skin characterized by numerous relapses. Eczematous patches, plaques, epidermal edema along with immunological cells in the infiltrate are the histologic features of eczema. It has been shown recently that CD4 and CD8 T-cells and the inflammatory cytokines such as IFN-γ, TNF-α, play a dominant role in the pathology of atopic dermatitis. Recent literature also suggests using biologics targeted to counter these pro-inflammatory cytokines. However, recently more focus has been put towards understanding the metabolic pathways of T-cell activation. Particular focus has been put in understanding the fatty acid metabolism involved in the T-cells.  It has been shown that T-cell activation leads to increased glucose uptake and activation of PI3K/AKT and mTOR pathway. Utilization of fatty acids for energy needs, i.e. using beta oxidation on the other hand leads to...