A cryptic tubulin-binding domain links MEKK1 to curved tubulin protomers
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Authors: Filipcik, Pavel; Latham, Sharissa L.; Cadell, Antonia L.; Day, Catherine L.; Croucher, David R.; Mace, Peter D.
Abstract
The MEKK1 protein is a pivotal kinase activator of responses to cellular stress. Activation of MEKK1 can trigger various responses, including mitogen-activated protein (MAP) kinases, NF-kappa B signaling, or cell migration. Notably, MEKK1 activity is triggered by microtubule-targeting chemotherapies, among other stressors. Here we show that MEKK1 contains a previously unidentified tumor overexpressed gene (TOG) domain. The MEKK1 TOG domain binds to tubulin heterodimers-a canonical function of TOG domains-but is unusual in that it appears alone rather than as part of a multi-TOG array, and has structural features distinct from previously characterized TOG domains. MEKK1 TOG demonstrates a clear preference for binding curved tubulin heterodimers, which exist in soluble tubulin and at sites of microtubule polymerization and depolymerization. Mutations disrupting tubulin binding decrease microtubule density at the leading edge of polarized cells, suggesting that tubulin binding may play a role in MEKK1 activity at the cellular periphery. We also show that MEKK1 mutations at the tubulin-binding interface of the TOG domain recur in patient-derived tumor sequences, suggesting selective enrichment of tumor cells with disrupted MEKK1-microtubule association. Together, these findings provide a direct link between the MEKK1 protein and tubulin, which is likely to be relevant to cancer cell migration and response to microtubule-modulating therapies.
An Anthocyanin-Enriched Extract from Vaccinium uliginosum Improves Signs of Skin Aging in UVB-Induced Photodamage
ANTIOXIDANTS
Authors: Jo, Kyungae; Bae, Gi Yeon; Cho, Kyoungwon; Park, Sung Sun; Suh, Hyung Joo; Hong, Ki-Bae
Abstract
Accumulating evidence indicates that botanical extracts affect skin biophysical parameters, such as hydration, transepidermal water loss (TEWL), melanin index, erythema index, and wrinkle development. Vaccinium uliginosum extract contains a high level of anthocyanins as antioxidant and is ideal for use in dietary skin care products. Here, we assessed the photoprotective effects of dietary V. uliginosum extract in ultraviolet B (UVB)-irradiated hairless mice. Quantitative analysis of anthocyanin composition in the ethanol-extracted V. uliginosum sample was performed using high-performance liquid chromatography (HPLC). Skin parameter analysis and hematoxylin and eosin (H&E) staining were conducted on skin samples from UVB-irradiated hairless mice to evaluate the effects of V. uliginosum extract on skin conditions. In addition, skin mRNA and protein expression were assessed to characterize the molecular mechanisms underlying the effects of the anthocyanin-enriched extract on skin appearance and condition. Administration of the ethanol-extracted V. uliginosum sample caused significant changes in skin water-holding capacity, TEWL, wrinkle-related parameters, and epidermal thickness in UVB-irradiated hairless mice. In addition, oral administration of V. uliginosum attenuated the gene expression of matrix metalloproteinase (MMP) and increased levels of tissue inhibitor of metalloproteinase (TIMP) and antioxidant-related genes. Further, V. uliginosum administration downregulated inflammatory cytokine levels and UVB-induced phosphorylation of extracellular signaling regulated kinase (ERK), as well as Jun N-terminal kinase (JNK) and p38 protein levels. Oral administration of anthocyanin-enriched V. uliginosum extract can improve the appearance and condition of the skin following UV irradiation.