Increased Susceptibility to Skin Carcinogenesis in TREX2 Knockout Mice.
TREX2 is a proofreading 3'-5' exonuclease that can be involved in genome maintenance; however, its biological role remains undefined. To better understand the function and physiologic relevance of TREX2, we generated mice deficient in TREX2 by targeted disruption of its unique coding exon. The knockout mice are viable and do not show relevant differences in growth, survival, lymphocyte development, or spontaneous tumor incidence compared with their wild-type counterparts over a period of up to 2 years. Also, we did not observe chromosomal instability or defects in cell proliferation and cell cycle upon loss of TREX2. We have observed that TREX2 expression is not ubiquitous, being expressed preferentially in tissues with stratified squamous epithelia, such as the skin or esophagus, and specifically in keratinocytes. Interestingly, TREX2-null mice are more susceptible to skin carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA) compared with wild-type mice. This phenotype correlates with a reduction of DMBA-induced apoptosis in both the epidermis and keratinocytes of TREX2-null mice. Altogether, our results suggest a tumor suppressor role for TREX2 in skin carcinogenesis through which it contributes to keratinocyte apoptosis under conditions of genotoxic stress.
Parra
David
D
Departament de Patologia i Terapèutica Experimental, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
Manils
Joan
J
Castellana
Bàrbara
B
Viña-Vilaseca
Arnau
A
Morán-Salvador
Eva
E
Vázquez-Villoldo
Nuria
N
Tarancón
Gemma
G
Borràs
Miquel
M
Sancho
Sara
S
Benito
Carmen
C
Ortega
Sagrario
S
Soler
Concepció
C
D015127:9,10-Dimethyl-1,2-benzanthracene; D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002273:Carcinogens; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005090:Exodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D014018:Tissue Distribution
D002273:Carcinogens; D015127:9,10-Dimethyl-1,2-benzanthracene; D005090:Exodeoxyribonucleases; C540589:Trex2 protein, mouse