Negative regulation of the FOXO3a transcription factor by mTORC2 induces a pro-survival response following exposure to ultraviolet-B irradiation

Abstract

Exposure to ultraviolet-B (UVB) irradiation, the principal cause of non-melanoma skin cancer (NMSC), activates both the rapamycin-sensitive mammalian target of rapamycin complex 1 (mTORC1) and the rapamycin-resistant mTORC2. We have previously reported that UVB-induced keratinocyte survival is dependent on mTORC2, though the specific mechanism is not well understood. FOXO3a is an important transcription factor involved in regulating cell survival. The activity of FOXO3a is reduced as a result of protein kinase B (AKT/PKB) activation, which is downstream of mTORC2; however, the specific function of FOXO3a during UVB-induced apoptosis is unclear. In this study, we establish that in cells with wild-type mTORC2 activity, FOXO3a is quickly phosphorylated in response to UVB and sequestered in the cytoplasm. In contrast, loss of mTORC2 causes FOXO3a to be localized to the nucleus and sensitizes cells to UVB-induced apoptosis. Furthermore, this sensitization is rescued by knockdown of FOXO3a. Taken together, these studies provide strong evidence that inhibition of mTORC2 enhances UVB-induced apoptosis in a FOXO3a-dependent manner, and suggest that FOXO3a activation by mTORC2 inhibitors may be a valuable chemopreventive target in NMSC.

Molecular signaling cascades involved in nonmelanoma skin carcinogenesis

“…As mentioned above, activation of various signaling pathways in the skin can occur as quickly as 5 minutes following exposure to UVR with peak activity occurring between 30 minutes to 1 hour on average [127–129]. The RTKs belong to an important family of receptors that are rapidly activated in response to UVR and have been linked to NMSC [24, 130, 131].…”

“…In addition, 14-3-3ζ binding masks two nuclear localization sequences on the FOXO3a [194], which along with two already exposed nuclear export signals, induces FOXO3a cytoplasmic localization and sequestration [195]. Our lab has recently demonstrated that knockdown of either rictor or mSIN1, two key structural components of mTORC2, sensitizes keratinocytes to UVB-induced apoptosis, and that this effect is dependent on AKT-mediated FOXO3a regulation [127]. Upon exposure to UVR, FOXO3a is shuttled out of the nucleus and sequestered into the cytoplasm.…”

Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease

“…Akt and 14-3-3 proteins not only repress the apoptotic roles of PACS-2 but also regulate other proapoptotic proteins, including the Bcl-2 protein Bad and FOXO transcription factors (Datta et al, 1997(Datta et al, , 2002Brunet et al, 1999;Singh et al, 2010;Feehan and Shantz, 2016). The regulation of Bad and FOXO proteins by Akt and 14-3-3 is akin to a simple molecular 'on or off' switch .…”

Erythropoietin and mTOR: A “One-Two Punch” for Aging-Related Disorders Accompanied by Enhanced Life Expectancy

“…mTOR oversees pathways of cell death through apoptosis and autophagy, two mechanisms that can determine cell survival through programmed cell death (105, 130, 131) (Table 1). Apoptosis results in the activation of nucleases and proteases involving caspases (132).…”

“…Loss of mTOR activity (105) or components of this pathway, such as mTORC2, can result in apoptotic cell death (130). Activation of either mTOR or downstream pathways that involve p70S6K can protect against Aβ toxicity (21, 25, 97, 117, 145–148), cerebral ischemia (149, 150), and oxidative stress exposure (151, 152).…”