主题：最近对各国政治领导力的一点感想 -- 仲明

Hedgehog signaling and its molecular perspective with cholesterol: a comprehensive review

Kaushal, JB (Kaushal, Jyoti B.) [1] ; Batra, SK (Batra, Surinder K.) [1] , [2] ; Rachagani, S (Rachagani, Satyanarayana) [1] , [2]

CELLULAR AND MOLECULAR LIFE SCIENCES

Hedgehog (Hh) signaling is evolutionarily conserved and plays an instructional role in embryonic morphogenesis, organogenesis in various animals, and the central nervous system organization. Multiple feedback mechanisms dynamically regulate this pathway in a spatiotemporal and context-dependent manner to confer differential patterns in cell fate determination. Hh signaling is complex due to canonical and non-canonical mechanisms coordinating cell-cell communication. In addition, studies have demonstrated a regulatory framework of Hh signaling and shown that cholesterol is vital for Hh ligand biogenesis, signal generation, and transduction from the cell surface to intracellular space. Studies have shown the importance of a specific cholesterol pool, termed accessible cholesterol, which serves as a second messenger, conveying signals between smoothened (Smo) and patched 1 (Ptch1) across the plasma and ciliary membranes. Remarkably, recent high-resolution structural and molecular studies shed new light on the interplay between Hh signaling and cholesterol in membrane biology. These studies elucidated novel mechanistic insight into the release and dispersal of cholesterol-anchored Hh and the basis of Hh recognition by Ptch1. Additionally, the putative model of Smo activation by cholesterol binding and/or modification and Ptch1 antagonization of Smo has been explicated. However, the coupling mechanism of Hh signaling and cholesterol offered a new regulatory principle in cell biology: how effector molecules of the Hh signal network react to and remodel cholesterol accessibility in the membrane and selectively activate Hh signaling proteins thereof. Recognizing the biological importance of cholesterol in Hh signaling activation and transduction opens the door for translational research to develop novel therapeutic strategies. This review looks in-depth at canonical and non-canonical Hh signaling and the distinct proposed model of cholesterol-mediated regulation of Hh signaling components, facilitating a more sophisticated understanding of the Hh signal network and cholesterol biology.

1 Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA

2 Univ Nebraska Med Ctr, Fred & Pamela Buffet Canc Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA

Intra-epithelial non-canonical Activin A signaling safeguards prostate progenitor quiescence

Cambuli, F (Cambuli, Francesco) [1] , [2] , [10] ; Foletto, V (Foletto, Veronica) [1] ; Alaimo, A (Alaimo, Alessandro) [1] ; De Felice, D (De Felice, Dario) [1] ; Gandolfi, F (Gandolfi, Francesco) [3] ; Palumbieri, MD (Palumbieri, Maria Dilia) [1] ; Zaffagni, M (Zaffagni, Michela) [1] ; Genovesi, S (Genovesi, Sacha) [1] ; Lorenzoni, M (Lorenzoni, Marco) [1] ; Celotti, M (Celotti, Martina) [1] ; Bertossio, E (Bertossio, Emiliana) [1] ; Mazzero, G (Mazzero, Giosue) [4] ; Bertossi, A (Bertossi, Arianna) [1] ; Bisio, A (Bisio, Alessandra) [1] ; Berardinelli, F (Berardinelli, Francesco) [5] , [6] ; Antoccia, A (Antoccia, Antonio) [5] ; Gaspari, M (Gaspari, Marco) [7] ; Barbareschi, M (Barbareschi, Mattia) [4] ; Fiorentino, M (Fiorentino, Michelangelo) [8] ; Shen, MM (Shen, Michael M.) [2] ; Loda, M (Loda, Massimo) [9] ; Romanel, A (Romanel, Alessandro) [3] ; Lunardi, A (Lunardi, Andrea) [1]

EMBO REPORTS

The healthy prostate is a relatively quiescent tissue. Yet, prostate epithelium overgrowth is a common condition during aging, associated with urinary dysfunction and tumorigenesis. For over thirty years, TGF-beta ligands have been known to induce cytostasis in a variety of epithelia, but the intracellular pathway mediating this signal in the prostate, and its relevance for quiescence, have remained elusive. Here, using mouse prostate organoids to model epithelial progenitors, we find that intra-epithelial non-canonical Activin A signaling inhibits cell proliferation in a Smad-independent manner. Mechanistically, Activin A triggers Tak1 and p38 MAPK activity, leading to p16 and p21 nuclear import. Spontaneous evasion from this quiescent state occurs upon prolonged culture, due to reduced Activin A secretion, a condition associated with DNA replication stress and aneuploidy. Organoids capable to escape quiescence in uitro are also able to implant with increased frequency into immunocompetent mice. This study demonstrates that non-canonical Activin A signaling safeguards epithelial quiescence in the healthy prostate, with potential implications for the understanding of cancer initiation, and the development of therapies targeting quiescent tumor progenitors.

1 Univ Trento, Dept Cellular Computat & Integrat Biol CIBIO, Armenise Harvard Lab Canc Biol & Genet, Trento, Italy

2 Columbia Univ, Irving Med Ctr, Herbert Irving Comprehens Canc Ctr, Dept Med Genet & Dev,Urol,Syst Biol, New York, NY 10027 USA

3 Univ Trento, Dept Cellular Computat & Integrat Biol CIBIO, Lab Bioinformat & Computat Genom, Trento, Italy

4 Santa Chiara Hosp APSS, Trento, Italy

5 Univ Roma Tre, Dept Sci, Rome, Italy

6 IRCCS Santa Lucia Fdn, Neurogenet & Mol Neurobiol Unit, Lab Neurodev, Rome, Italy

7 Univ Catanzaro, Dept Expt & Clin Med, Catanzaro, Italy

8 Univ Bologna, Dept Expt Diagnost & Specialty Med, Bologna, Italy

9 Cornell Univ, Dept Pathol & Lab Med, Weill Med Coll, New York, NY USA

10 Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Mol Pharmacol Program, 1275 York Ave, New York, NY 10021 USA