Background: P311 is a stimulator of TGF-␤1-3 translation, but its mechanism of action is unknown. Results: P311 binds eIF3b and the 5ЈUTRs of TGF-␤1-3 mRNAs. Thereby, P311 recruits TGF-␤1-3 mRNAs to the translation machinery. Conclusion: P311 is an RNA-binding protein that binds to eIF3b to stimulate TGF-␤1-3 translation. Significance: Our studies add a new level of complexity to TGF-␤ signaling regulation.

Neuronal protein 3.1 (P311), a conserved RNA-binding protein, represents the first documented protein known to stimulate transforming growth factor (TGF)-b1 to -b3 translation in vitro and in vivo. Because TGF-bs play critical roles in fibrogenesis, we initiated efforts to define the role of P311 in skin scar formation. Here, we show that P311 is up-regulated in skin wounds and in normal and hypertrophic scars. Genetic ablation of p311 resulted in a significant decrease in skin scar collagen deposition. Lentiviral transfer of P311 corrected the deficits, whereas down-regulation of P311 levels by lentiviral RNA interference reproduced the deficits seen in P311 À/À mice. The decrease in collagen deposition resulted in scars with reduced stiffness but also reduced scar tensile strength. In vitro studies using murine and human dermal fibroblasts showed that P311 stimulated TGF-b1 to -b3 translation, a process that involved eukaryotic translation initiation factor 3 subunit b as a P311 binding partner. This resulted in increased TGF-b levels/activity and increased collagen production. In addition, P311 induced dermal fibroblast activation and proliferation. Finally, exogenous TGF-b1 to -b3, each restituted the normal scar phenotype. These studies demonstrate that P311 is required for the production of normal cutaneous scars and place P311 immediately up-stream of TGF-bs in the process of fibrogenesis. Conditions that decrease P311 levels could result in less tensile scars, which could potentially lead to higher incidence of dehiscence after surgery. (Am J Pathol 2017, 187: 292e303; http://dx

Lymphangioleiomyomatosis (LAM) of the lung is a rare low-grade malignancy affecting primarily women of childbearing age. LAM is characterized by the proliferation of SMA and HMB-45 positive spindle-shaped and epithelioid cells throughout the lung in the form of discrete lesions causing cystic destruction and ultimately respiratory insufficiency. LAM occurs sporadically or in patients with tuberous sclerosis complex (TSC) and is etiologically linked to mutations in the TSC1 and TSC2 genes. Although LAM cells are known to express estrogen and progesterone receptors (ER and PR, respectively), their respective expression level was never determined. Therefore, here we measured the immunohistochemical expression of ERs and PRs in a large series of pulmonary LAM cases using the Aperio Spectrum Analysis Platform. Our case series comprised open lung biopsy specimens from 20 LAM patients and lungs explanted during the course of lung transplant from 24 patients. All cases were positive for ER and PR. PR expression was statistically significantly higher than ER in 80 % of the biopsies while ER predominated only in one case. Specimens from explanted cases of LAM had relatively fewer PR-positive nuclei. As a result, PR expression was significantly higher than ER in 38 % of the cases, whereas ER predominated in 33 %. Overall, PR expression predominated in 57 % of cases and ER in 21 %. These data indicate that PR frequently prevails over ER in pulmonary LAM. LAM is unusual in its high PR/ER ratio; other female neoplasms show a definite prevalence of ER. Our findings therefore warrant further study of PR function in LAM.

Angiomyolipoma (AML) is a tumor closely related to lymphangioleiomyomatosis (LAM). Both entities are characterized by the proliferation of smooth muscle actin and melanocytic glycoprotein 100 (recognized by antibody HMB-45)epositive spindle-shaped and epithelioid cells. AML and LAM are etiologically linked to mutations in the tsc2 and tsc1 genes in the case of LAM. These genes encode the proteins tuberous sclerosis complex (TSC)-1 and TSC2, which are directly involved in suppressing the mechanistic target of rapamycin cell growth signaling pathway. Although significant progress has been made in characterizing and pharmacologically slowing the progression of AML and LAM with rapamycin, our understanding of their pathogenesis lacks an identified cell of origin. We used an AML-derived cell line to determine whether TSC2 restitution brings about the cell type from which AML arises. We found that AML cells express lymphatic endothelial cell markers consistent with lymphatic endothelial cell precursors in vivo and in vitro. Moreover, on TSC2 correction, AML cells mature into adult lymphatic endothelial cells and have functional attributes characteristic of this cell lineage, suggesting a lymphatic endothelial cell of origin for AML. These effects are dependent on TSC2-mediated mechanistic target of rapamycin inactivation. Finally, we demonstrate the in vitro effectiveness of norcantharidin, a lymphangiogenesis inhibitor, as a potential co-adjuvant therapy in the treatment of AML. (Am J Pathol 2016 http://dx