The phosphatase and tensin homolog (PTEN) gene was identified in 1997 as a tumor suppressor gene capable of antagonizing proto-oncogenes as the PI3K (Maehama and Dixon, 1998) (Maehama, 2007) (Stambolic et al, 1998). This phosphatase has as a substrate PIP3 that is dephosphorylated into PIP2, which results in the controlling of the AKT signaling activation. As a major regulator of the PI3K signaling, the role of PTEN in the control of physiological and pathological processes is becoming increasingly clear. This is the case for autoimmunity and lymphomagenesis (Newton and Turka, 2012), innate immune responses in mouse liver ischemia (Kamo et al, 2012), normal lung morphogenesis, and the prevention of lung carcinogenesis (Yanagi et al, 2007). Of interest for this review, in skin homeostasis loss of Pten results in progressive changes in the hair follicles with increased thickness of the outer root sheet and the development of multiple hyperproliferative lesions throughout the skin, especially around the nose, mouth, eyes, paws, limbs, and mucosa (Squarize et al, 2008). Such loss of function over the control of cellular proliferation caused by deletion of Pten denotes the importance of this tumor suppressor gene for the maintenance of tissue homeostasis, yet also indicates that transient downregulation of this tumor suppressive pathway may be of interest for regenerative therapies. Indeed, we have previously shown that excision of Pten from the epidermis using a CRE recombinase driven by the cytokeratin 14 promoter can dramatically influence the recovery of a wounded skin by accelerating the healing process (Fig. 1) (Squarize et al, 2010). As expected, deletion of Pten results in over activity of the PI3K signaling pathway and activation of the phosphorylated Akt and pS6 (Fig. 2) in the wounded area. Expression of active Akt and pS6, typically observed in the superficial layers of the epidermis (stratum corneum), was promptly upregulated in the spinous and partially in the basal layer at the transition skin, which is localized between normal skin and the wound edge. Akt and pS6 (Fig. 2) were further upregulated at the epithelial tongue throughout the entire thickness of the epidermis. Skin wounds from control mice also demonstrate an upregulation of Akt and pS6 in the transition and epithelial tongue, however much better compartmentalized within the differentiated layers of the epidermis than mice presenting deletion of Pten (Fig. 2) (Squarize et al, 2010). These findings suggest that physiological downregulation of Pten may be required for proper skin healing and that further downregulation of other members of the PI3K signaling pathway, aiming at the activating mTOR, may also be a viable strategy to influence skin regeneration while preventing unwanted side effects.
Figure 1. Absence of Pten from epithelial cells of the skin resulted in accelerated wound healing. Pten is the main regulator of the PI3K/mTOR pathway. With the excision of Pten, epithelial cells proliferate and migrate faster than the epithelial cells from control mice. Accordingly, skin healing from K14Cre PtenF/F is dramatically accelerated after incisional surgical wounding. As seen here, wound closure of mice group with Pten epithelial-specific conditional deletion was completed by day 9, while control group exhibited wound closure by day 12 (P < 0.0001, n = 8) (data are from Squarize et al, 2010).
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Figure 2. mTOR pathway is activated during the wound healing process. Upregulation of mTOR (pS6) is found in the transitional and epithelial tongue correspondent to the proliferative and migratory anatomical areas of normal wounds. In addition, histological analyses of the wounds demonstrate the upregulation of mTOR signaling on epithelial cells derived from Pten and Tsc1 deletion (K14Cre PtenF/F and K14Cre Tsc1F/F mice, respectively), which resulted in increased re-epithelization. (pS6, red (TRICT); fibrin clot, green (FITC); cells/nucleus, blue (DAPI) (data are from Squarize et al, 2010).
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