title: Expression of cell proliferation cycle negative regulators in fibroblasts of an ischemic diabetic foot ulcer. A clinical case report.
abstract: Wound chronification and opportunistic infections stand as major factors leading to lower extremities amputations in diabetes. The molecular mechanisms underlying diabetic's torpid healing have not been elucidated. We present the case of a female diabetic patient that after a plantar abscess surgical drainage, tight glycaemia control and infection clearance; the wound bed evolved to chronification with poor matrix accumulation, scant angiogenesis and no evidence of dermo-epidermal contours contraction. Ulcer fibroblasts yet cultured under 'physiological' conditions exhibited a slow and declining proliferative response. Diabetic fibroblasts cycle arrest occurred earlier than non-diabetic counterparts. This in vitro premature arrest-senescence phenotype appeared related to the transcriptional upregulation of p53 and the proto-oncogene c-myc; with a concomitant expression reduction of the survival and cellular growth promoters Akt and mTOR. Importantly, immunocytochemistry of the diabetic ulcer-derived fibroblasts proved nuclear over expression of potent proliferation inhibitors and pro-senescence proteins as p53 phosphorylated on serine-15 and p21(Cip) (1). In line with this, cyclin D1 appeared substantially underexpressed in these cells. We postulate that the downregulation of the Akt/mTOR/cyclin D1 axis by the proximal activation of p53 and p21 due to stressor factors, impose an arrest/pro-senescence programme that translated in a torpid and slow healing process.
authors.affiliation: Tissue repair and cytoprotection project, Biomedical Direction, Center for Genetic Engineering and Biotechnology, Havana, Cuba. jorge.berlanga@cigb.edu.cu
authors.forename: Jorge
authors.initials: J
authors.lastname: Berlanga-Acosta
authors.forename: Yssel
authors.initials: Y
authors.lastname: Mendoza-Mari
authors.forename: María Daniela
authors.initials: MD
authors.lastname: Martínez
authors.forename: Calixto
authors.initials: C
authors.lastname: Valdés-Perez
authors.forename: Ariana G
authors.initials: AG
authors.lastname: Ojalvo
authors.forename: David G
authors.initials: DG
authors.lastname: Armstrong
mesh_terms: D000368:Aged; D049109:Cell Proliferation; D016922:Cellular Senescence; D017719:Diabetic Foot / Q000150:complications / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D000090063:Proto-Oncogene Mas; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014945:Wound Healing; D014946:Wound Infection / Q000209:etiology / Q000517:prevention & control*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016159:Tumor Suppressor Protein p53