Differential Role of the RasGEFs Sos1 and Sos2 in Mouse Skin Homeostasis and Carcinogenesis

Autor: Jesús M. Paramio, Mauricio Menacho-Márquez, Nuria Calzada, Xosé R. Bustelo, Carmela Gómez, P. Liceras-Boillos, Rocío Fuentes-Mateos, Rósula García-Navas, Eugenio Santos, Fernando C. Baltanás, Carmen Segrelles, L. Francisco Lorenzo-Martín, David Jimeno
Přispěvatelé: Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Junta de Castilla y León, Asociación Española Contra el Cáncer, European Commission
Rok vydání: 2018
Předmět:
0301 basic medicine
Skin Neoplasms
Carcinogenesis
Adipose tissue
DMBA
Neovascularization
Physiologic
Tumor initiation
Biology
medicine.disease_cause
DMBA/TPA
SKIN TUMORS
Ciencias Biológicas
purl.org/becyt/ford/1 [https]
03 medical and health sciences
Mice
Dermis
WOUND REPAIR
Cell Movement
medicine
Animals
Homeostasis
Skin tumors: Sos1: Sos2: Wound repair [RasGEFs]
SOS1
SOS2
purl.org/becyt/ford/1.6 [https]
Molecular Biology
Cell Proliferation
Skin
Mice
Knockout
Wound Healing
integumentary system
Papilloma
RasGEFs: Skin tumors: Sos1: Sos2: Wound repair
RASGEFS
Cell Biology
Bioquímica y Biología Molecular
Hair follicle
030104 developmental biology
medicine.anatomical_structure
Cell Transformation
Neoplastic
Son of Sevenless Proteins
Cancer research
Keratinocyte
SOS1 Protein
CIENCIAS NATURALES Y EXACTAS
Research Article
Zdroj: CONICET Digital (CONICET)
Consejo Nacional de Investigaciones Científicas y Técnicas
instacron:CONICET
Digital.CSIC: Repositorio Institucional del CSIC
Consejo Superior de Investigaciones Científicas (CSIC)
Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 1098-5549
Popis: Using Sos1 knockout (Sos1-KO), Sos2-KO, and Sos1/2 double-knockout (Sos1/2-DKO) mice, we assessed the functional role of Sos1 and Sos2 in skin homeostasis under physiological and/or pathological conditions. Sos1 depletion resulted in significant alterations of skin homeostasis, including reduced keratinocyte proliferation, altered hair follicle and blood vessel integrity in dermis, and reduced adipose tissue in hypodermis. These defects worsened significantly when both Sos1 and Sos2 were absent. Simultaneous Sos1/2 disruption led to severe impairment of the ability to repair skin wounds, as well as to almost complete ablation of the neutrophil-mediated inflammatory response in the injury site. Furthermore, Sos1 disruption delayed the onset of tumor initiation, decreased tumor growth, and prevented malignant progression of papillomas in a DMBA (7,12-dimethylbenz[α]anthracene)/TPA (12-O-tetradecanoylphorbol-13-acetate)-induced skin carcinogenesis model. Finally, Sos1 depletion in preexisting chemically induced papillomas resulted also in decreased tumor growth, probably linked to significantly reduced underlying keratinocyte proliferation. Our data unveil novel, distinctive mechanistic roles of Sos 1 and Sos2 in physiological control of skin homeostasis and wound repair, as well as in pathological development of chemically induced skin tumors. These observations underscore the essential role of Sos proteins in cellular proliferation and migration and support the consideration of these RasGEFs as potential biomarkers/therapy targets in Ras-driven epidermal tumors.
This study was supported by grants FIS PI16/02137 from ISCIII (MINECO), SA043U16 (UIC 076) from JCyL, and AECC Spain (to E.S.); by MINECO grant SAF2015-66015-R; and by MSyC grants ISCIII-RETIC RD12/0036/0009, PIE 15/00076, and CB/16/00228 (to J.M.P.). This research was cofinanced by FEDER funds
Databáze: OpenAIRE
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