研究领域

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1) Functional characterization of the FLCN-AMPK pathway in cancer - The Birt-Hogg-Dubé (BHD) syndrome is a hereditary human cancer syndrome that predisposes affected individuals to develop renal carcinoma of nearly all subtypes, as well as benign fibrofolliculomas, pulmonary, colon and renal cysts, caused by loss of-function mutations in the FLCN gene. FLCN was identified as an AMPK binding partner, and we demonstrated that FLCN is an evolutionarily conserved negative regulator of AMPK. Loss of FLCN constitutively activated AMPK, resulting in PGC-1α-mediated mitochondrial biogenesis, increased ROS production, which induced HIF transcriptional activity and drove Warburg metabolic reprogramming. This reprogramming stimulated cellular bioenergetics and conferred a HIF-dependent tumorigenic advantage in FLCN-negative cancer cells. Moreover, using Caenorhabditis elegans and mammalian cells, we showed that loss of FLCN results in constitutive AMPK-dependent induction of autophagy, inhibition of apoptosis, enhanced cellular bioenergetics, and resistance to energy-depleting stresses including oxidative stress, heat, anoxia, and serum deprivation. We further showed that AMPK activation conferred by FLCN loss is independent of the cellular energy state suggesting that FLCN controls the AMPK energy sensing ability. Together, our data suggest that FLCN is an evolutionarily conserved regulator of AMPK signaling that acts as a tumor suppressor by negatively regulating AMPK function. We are now studying the mechanism of FLCN inhibition with respect to AMPK sensing activity as well as the effect of FLCN loss and AMPK activation in tumor progression in various human cancers. 2) Role of ESCRT component HD-PTP/PTPN23 in cancer - Components of the Endosomal Sorting Complexes Required for Transport (ESCRT) have long been proposed to act as tumor suppressors. PTPN23 or HD-PTP, an ESCRT associated protein, is located on 3p21.3, a region frequently deleted in many human malignancies. Previously, we have demonstrated that HD-PTP is a catalytically inactive PTP due to an evolutionary conserved divergence in its phosphatase domain. Using a mouse model we showed that HD-PTP is expressed in all epithelial tissues and that homozygous deletion of Ptpn23 is embryonic lethal at day 9.5. We are now characterizing various cancer phenotypes in this mouse model to elucidate the function of HD-PTP in tumorigenesis. We are also studying the effect of HD-PTP depletion on cell surface receptor trafficking, by elucidating the molecular determinants of endocytosed receptors targeting for recycling or lysosomal delivery such as receptor ubiquitination and deubiquitination. ESCRT machinery is responsible for lysosomal targeting of ubiquitinated receptors, which leads to their signal abrogation. Therefore, depletion of ESCRT components is likely to result in enhanced recycling and downstream signalling of receptors escaping degradation, potentially leading to enhanced tumor initiation and progression.