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Renal cell carcinoma (RCC) is the most common kidney cancer in humans. Misregulation of the Hippo/Warts pathway is frequently reported in RCC, suggesting a role in disease formation/progression. Paradoxically, misregulation of this pathway is also observed in non-tumorigenic kidney diseases, raising questions as to its specific role in RCC. Here, we show that ablation of the Warts kinases Lats1 and Lats2 in mature renal epithelia was sufficient to cause metastatic RCC in mice. Distinct tumors with sarcomatoid histology were present in mutant kidneys 3 months after genetic ablation. Tumor formation required the downstream effectors Yap and Taz, and treatment with verteporfin, a drug that inhibits Yap activity, could slow progression of the disease. Examination of human tissues showed that among histological subtypes of RCC, nuclear YAP was most commonly observed in sarcomatoid RCC. However, analysis of transcriptomic data from human RCC revealed a unique subset with a molecular signature that closely resembled the transcriptome of Lats mutants. Together, these findings show that misregulation of the Warts pathway is sufficient to drive renal tumor formation in mice and suggest that human tumors with active YAP may represent a unique subset of RCCs that can be therapeutically targeted., Introduction The Hippo/Warts (Mst/Lats) pathway is one of the major signaling pathways regulating organ size and tissue growth during embryonic development (1). The pathway controls the activity of several genes [...]

The Staphylococcus aureus gene cluster responsible for producing the prevalent siderophore staphyloferrin A is characterized. Two nonribosomal peptide synthetase independent siderphore (NIS) synthetases have condensed two molecules of citric acid to D-ornithine in a stepwise ordered process with SfnaD by using [delta]-amine as a nucleophile to form the first amide followed by SfnaB using the [alpha]-amine to complete staphyloferrin A synthesis.

Administrative Judges (AJs) are a large and often overlooked group of federal agency adjudicators. While courts have examined Article II Appointments Clause challenges to Administrative Law Judges (ALJs), courts have yet to encounter a legal challenge to the constitutionality of AJs' appointment procedures. The constitutionality of any federal government actor's appointment is dependent upon whether that actor is an "officer" or an "employee" under the Article II Appointments clause. It is apparent that the current "significant authority" test that the Supreme Court has espoused to distinguish between officers and employees is unworkable. This Note endeavors to set forth a brightline test to distinguish between officers and employees that better serves the purposes of the Appointments Clause and is more easily applicable. The test is simple: if an AJ is "established by Law," then that AJ is an officer and must be appointed according to the Appointments Clause. [ABSTRACT FROM AUTHOR]

Studies on Hippo pathway regulation of tumorigenesis largely center on YAP and TAZ, the transcriptional co-regulators of TEAD. Here, we present an oncogenic mechanism involving VGLL and TEAD fusions that is Hippo pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-NCOA2 and TEAD1-NCOA2, recently identified in spindle cell rhabdomyosarcoma. We demonstrate that, in contrast to VGLL2 and TEAD1, the fusion proteins are strong activators of TEAD-dependent transcription, and their function does not require YAP/TAZ. Furthermore, we identify that VGLL2 and TEAD1 fusions engage specific epigenetic regulation by recruiting histone acetyltransferase p300 to control TEAD-mediated transcriptional and epigenetic landscapes. We showed that small molecule p300 inhibition can suppress fusion proteins-induced oncogenic transformation both in vitro and in vivo . Overall, our study reveals a molecular basis for VGLL involvement in cancer and provides a framework for targeting tumors carrying VGLL, TEAD, or NCOA translocations., Competing Interests: Disclosure and competing interests statement Conflict of Interest: Dr. Xu Wu has a financial interest in Tasca Therapuetics, which is developing small molecule modulators of TEAD palmitoylation and transcription factors. Dr. Wu’s interests were reviewed and are managed by Mass General Hospital, and Mass General Brigham in accordance with their conflict of interest policies.