Scaffold proteins of cancer signaling networks: The paradigm of FK506 binding protein 51 (FKBP51) supporting tumor intrinsic properties and immune escape

Scaffold proteins are crucial regulators of signaling networks,and their abnormal expression may favor the development of tumors.Among the scaffold proteins,immunophilin covers a unique role as‘protein-philin’(Greek‘philin’=friend)that interacts with proteins to guide their proper assembly.The growing list of human syndromes associated with the immunophilin defect underscores the biological relevance of these proteins that are largely opportunistically exploited by cancer cells to support and enable the tumor’s intrinsic properties.Among the members of the immunophilin family,the FKBP5 gene was the only one identified to have a splicing variant.Cancer cells impose unique demands on the splicing machinery,thus acquiring a particular susceptibility to splicing inhibitors.This review article aims to overview the current knowledge of the FKBP5 gene functions in human cancer,illustrating how cancer cells exploit the scaffolding function of canonical FKBP51 to foster signaling networks that support their intrinsic tumor properties and the spliced FKBP51s to gain the capacity to evade the immune system.

AtFKBP53 is a histone chaperone required for repression of ribosomal RNA gene expression in Arabidopsis

Chromatin structure is important for controlling gene expression, but mechanisms underlying chromatin remodel- ing are not fully understood. Here we report that an FKBP （FK506 binding protein） type immunophilin, AtFKBP53, possesses histone chaperone activity and is required for repressing ribosomal gene expression in Arabidopsis. The At- FKBP53 protein is a multidomain FKBP with a typical peptidylprolyl isomerase （PPIase） domain and several highly charged domains. Using nucleosome assembly assays, we showed that AtFKBP53 has histone chaperone activity and the charged acidic domains are sufficient for the activity. We show that AtFKBP53 interacts with histone H3 through the acidic domains, whereas the PPIase domain is dispensable for histone chaperone activity or histone binding. Ri- bosomal RNA gene （18S rDNA） is overexpressed when AtFKBP53 activity is reduced or eliminated in Arabidopsis plants. Chromatin immunoprecipitation assay showed that AtFKBP53 is associated with the 18S rDNA gene chro- matin, implicating that AtFKBP53 represses rRNA genes at the chromatin level. This study identifies a new histone chaperone in plants that functions in chromatin remodeling and regulation of transcription.

Emerging neuromodulatory molecules for the treatment of neurogenic erectile dysfunction caused by cavernous nerve injury

Advances in the neurobiology of growth factors, neural development, and prevention of cell death have resulted in a heightened clinical interest for the development of protective and regenerative neuromodulatory strategies for the cavernous nerves （CNs）, as therapies for prostate cancer and other pelvic malignancies often result in neuronal damage and debilitating loss of sexual function. Nitric oxide released from the axonal end plates of these nerves within the corpora cavernosa causes relaxation of smooth muscle, initiating the haemodynamic changes of penile erection as well as contributing to maintained tumescence; the loss of CN function is primarily responsible for the development of erectile dysfunction （ED） after pelvic surgery and serves as the primary target for potential neuroprotective or regenerative strategies. Evidence from pre-clinical studies for select neuromodulatory approaches is reviewed, including neurotrophins, glial cell line-derived neurotrophic factors （GDNF）, bone morphogenic proteins, immunophilin ligands, erythropoetin （EPO）, and stem cells.

The immunophilin CYCLOPHILIN28 affects PSII-LHCII supercomplex assembly and accumulation in Arabidopsis thaliana

In plant chloroplasts,photosystem II(PSII)complexes,together with light-harvesting complex II(LHCII),form various PSII-LHCII supercomplexes(SCs).This process likely involves immunophilins,but the underlying regulatory mechanisms are unclear.Here,by comparing Arabidopsis thaliana mutants lacking the chloroplast lumen-localized immunophilin CYCLOPHILIN28(CYP28)to wildtype and transgenic complemented lines,we determined that CYP28 regulates the assembly and accumulation of PSII-LHCII SCs.Compared to the wild type,cyp28 plants showed accelerated leaf growth,earlier flowering time,and enhanced accumulation of high molecular weight PSII-LHCII SCs under normal light conditions.The lack of CYP28 also significantly affected the electron transport rate.Blue native-polyacrylamide gel electrophoresis analysis revealed more Lhcb6 and less Lhcb4 in M-LHCII-Lhcb4-Lhcb6 complexes in cyp28 versus wild-type plants.Peptidyl-prolyl cis/trans isomerase(PPIase)activity assays revealed that CYP28 exhibits weak PPIase activity and that its K113 and E187 residues are critical for this activity.Mutant analysis suggested that CYP28 may regulate PSIILHCII SC accumulation by altering the configuration of Lhcb6 via its PPIase activity.Furthermore,the Lhcb6-P139 residue is critical for PSII-LHCII SC assembly and accumulation.Therefore,our findings suggest that CYP28 likely regulates PSII-LHCII SC assembly and accumulation by altering the configuration of P139 of Lhcb6 via its PPIase activity.