Increased osteoclastogenesis contributes to bone loss in the Costello syndrome mouse model.

RAS GTPases are ubiquitous GDP/GTP-binding proteins that function as molecular switches in cellular signalling and control numerous signalling pathways and biological processes. Pathogenic mutations in genes severely affect cellular homeostasis, leading to cancer when occurring in somatic cells and developmental disorders when the germline is affected. These disorders are generally termed as RASopathies and among them Costello syndrome (CS) is a distinctive entity that is caused by specific germline mutations.

The glucocorticoid receptor associates with RAS complexes to inhibit cell proliferation and tumor growth.

Mutations that activate members of the RAS family of GTPases are associated with various cancers and drive tumor growth. The glucocorticoid receptor (GR), a member of the nuclear receptor family, has been proposed to interact with and inhibit the activation of components of the PI3K-AKT and MAPK pathways downstream of RAS. In the absence of activating ligands, we found that GR was present in cytoplasmic KRAS-containing complexes and inhibited the activation of wild-type and oncogenic KRAS in mouse embryonic fibroblasts and human lung cancer A549 cells.

Studying Metabolic Abnormalities in the Costello Syndrome HRAS G12V Mouse Model: Isolation of Mouse Embryonic Fibroblasts and Their In Vitro Adipocyte Differentiation.

Costello syndrome (CS), characterized by a developmental delay and a failure to thrive, is also associated with an impaired lipid and energy metabolism. White adipose tissue is a central sensor of whole-body energy homeostasis, and HRAS hyperactivation may affect adipocyte differentiation and mature adipocyte homeostasis. An extremely useful tool for delineating in vitro intrinsic cellular signaling leading to metabolic alterations during adipogenesis is mouse embryonic fibroblasts, known to differentiate into adipocytes in response to adipogenesis-stimulating factors.

Senescence in RASopathies, a possible novel contributor to a complex pathophenoype.

Senescence is a biological process that induces a permanent cell cycle arrest and a specific gene expression program in response to various stressors. Following studies over the last few decades, the concept of senescence has evolved from an antiproliferative mechanism in cancer (oncogene-induced senescence) to a critical component of physiological processes associated with embryonic development, tissue regeneration, ageing and its associated diseases. In somatic cells, oncogenic mutations in RAS-MAPK pathway genes are associated with oncogene-induced senescence and cancer, while germline mutations in the same pathway are linked to a group of monogenic developmental disorders generally termed RASopathies.

Local and transient inhibition of p21 expression ameliorates age-related delayed wound healing.

Nonhealing chronic wounds in the constantly growing elderly population represent a major public health problem with high socioeconomic burden. Yet, the underlying mechanism of age-related impairment of wound healing remains elusive. Here, we show that the number of dermal cells expressing cyclin-dependent kinase inhibitor p21 was elevated upon skin injury, particularly in aged population, in both man and mouse.

Cdk5 Deletion Enhances the Anti-inflammatory Potential of GC-Mediated GR Activation During Inflammation.

The suppression of activated pro-inflammatory macrophages during immune response has a major impact on the outcome of many inflammatory diseases including sepsis and rheumatoid arthritis. The pro- and anti-inflammatory functions of macrophages have been widely studied, whereas their regulation under immunosuppressive treatments such as glucocorticoid (GC) therapy is less well-understood. GC-mediated glucocorticoid receptor (GR) activation is crucial to mediate anti-inflammatory effects.

Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling.

Noonan syndrome (NS), the most common RASopathy, is caused by mutations affecting signaling through RAS and the MAPK cascade. Recently, genome scanning has discovered novel genes implicated in NS, whose function in RAS-MAPK signaling remains obscure, suggesting the existence of unrecognized circuits contributing to signal modulation in this pathway. Among these genes, leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a functionally poorly characterized member of the BTB/POZ protein superfamily.