The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis.

A complex interaction of signalling events, including the Wnt pathway, regulates sprouting of blood vessels from pre-existing vasculature during angiogenesis. Here we show that two distinct mutations in the (uro)chordate-specific gumby (also called Fam105b) gene cause an embryonic angiogenic phenotype in gumby mice. Gumby interacts with disheveled 2 (DVL2), is expressed in canonical Wnt-responsive endothelial cells and encodes an ovarian tumour domain class of deubiquitinase that specifically cleaves linear ubiquitin linkages. A crystal structure of gumby in complex with linear diubiquitin reveals how the identified mutations adversely affect substrate binding and catalytic function in line with the severity of their angiogenic phenotypes. Gumby interacts with HOIP (also called RNF31), a key component of the linear ubiquitin assembly complex, and decreases linear ubiquitination and activation of NF-κB-dependent transcription. This work provides support for the biological importance of linear (de)ubiquitination in angiogenesis, craniofacial and neural development and in modulating Wnt signalling.

Low-Level Light Therapy and Minoxidil Combination Treatment in Androgenetic Alopecia: A Review of the Literature.

Introduction: We analyzed randomized clinical trials (RCTs) evaluating the efficacy of combined therapy with low-level light therapy (LLLT) and topical minoxidil for treatment of androgenetic alopecia (AGA). Methods: A literature search within PubMed identified RCTs evaluating hair regrowth following LLLT and minoxidil. Selection criteria were 600-1,100 nm wavelengths, treatment time ≥16 weeks, and objective evaluation for hair regrowth. Results: Five RCTs compared LLLT with minoxidil (2% or 5%) to 5% minoxidil treatment or LLLT treatment. One study showed combination therapy of LLLT, and 5% minoxidil improved hair density more than monotherapy. Another found combination LLLT with 2% minoxidil induced hair regrowth equivalent to 5% minoxidil. Similarly, another study described LLLT with 5% minoxidil versus minoxidil monotherapy to increase the number of hairs with no statistical difference between groups. One trial found that combination group increased hair regrowth in the first 2 months. The last study found a statistically significant increase in hair density with combined therapy compared to monotherapy. Conclusion: The studies describe either superiority or equivalence of combination therapy to minoxidil monotherapy for AGA. Early outcomes appear to support the superiority of combination therapy, but this advantage wanes at the end of the study periods.

An interaction between OTULIN and SCRIB uncovers roles for linear ubiquitination in planar cell polarity.

Planar cell polarity (PCP) plays critical roles in developmental and homeostatic processes. Membrane presentation of PCP complexes containing Van Gogh-like (VANGL) transmembrane proteins is central to PCP and can be directed by the scaffold protein scribble (SCRIB). The role atypical linear ubiquitin (Met1-Ub) chains might play in PCP is unknown. Here, HEK293 cell-based interactomic analyses of the Met1-Ub deubiquitinase OTULIN revealed that OTULIN can interact with SCRIB. Moreover, Met1-Ub chains associated with VANGL2 and PRICKLE1, but not SCRIB, can direct VANGL2 surface presentation. Mouse embryos lacking Otulin showed variable neural tube malformations, including rare open neural tubes, a deficit associated with PCP disruption in mice. In Madin-Darby canine kidney cells, in which the enrichment of VANGL2-GFP proteins at cell-cell contacts represents activated PCP complexes, endogenous OTULIN was recruited to these sites. In the human MDA-MB-231 breast cancer cell model, OTULIN loss caused deficits in Wnt5a-induced filopodia extension and trafficking of transfected HA-VANGL2. Taken together, these findings support a role for linear (de)ubiquitination in PCP signaling. The association of Met1-Ub chains with PCP complex components offers new opportunities for integrating PCP signaling with OTULIN-dependent immune and inflammatory pathways.

The Application of GHRH Antagonist as a Treatment for Resistant APL.

GHRH is a hypothalamic peptide shown to stimulate the proliferation of malignant cells in humans. We have previously shown that the use of GHRH antagonist MIA-602 successfully suppressed the growth of many human cancer cell lines, spanning more than 20 types of cancers. In this study, we demonstrate the presence of GHRH-R in the NB4, NB4-RAA, and K-562 model cell lines. Furthermore, we demonstrate the inhibited proliferation of all three cell lines in vitro after incubation with MIA-602. The treatment of xenografts of human APL cell lines with MIA-602 led to a significant reduction in tumor growth. Additionally, combination therapy with both doxorubicin (DOX) and MIA-602 showed a marked synergistic effect in reducing the proliferation of the K-562 AML cell line. These findings suggest that MIA-602 could be utilized to address resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) therapies, as well as in augmenting anthracycline-based regimens.