Functional Activation of ATM by the Prostate Cancer Suppressor NKX3.1
Menée in vitro, cette étude met en évidence un mécanisme par lequel, en régulant la réponse des cellules épithéliales de la prostate à un dégât de l'ADN, le gène NKX3.1 joue un rôle de suppresseur de tumeurs
The prostate tumor suppressor NKX3.1 augments response to DNA damage and enhances survival after DNA damage. Within minutes of DNA damage, NKX3.1 undergoes phosphorylation at tyrosine 222, which is required for a functional interaction with ataxia telangiectasia mutated (ATM) kinase. NKX3.1 binds to the N-terminal region of ATM, accelerates ATM activation, and hastens the formation of ³histone2AX. NKX3.1 enhances DNA-dependent ATM kinase activation by both the MRN complex and H2O2 in a DNA-damage-independent manner. ATM, bound to the NKX3.1 homeodomain, phosphorylates NKX3.1, leading to ubiquitination and degradation. Thus, NKX3.1 and ATM have a functional interaction leading to ATM activation and then NKX3.1 degradation in a tightly regulated DNA damage response specific to prostate epithelial cells. These findings demonstrate a mechanism for the tumor-suppressor properties of NKX3.1, demonstrate how NKX3.1 may enhance DNA integrity in prostate stem cells and may help to explain how cells differ in their sensitivity to DNA damage. "The prostate tumor suppressor NKX3.1 affects DNA damage response and cell survival "NKX3.1 undergoes tyrosine phosphorylation within minutes of DNA damage "NKX3.1 binds to ATM and activates ATM kinase "ATM phosphorylates NKX3.1 leading to ubiquitination and degradation after DNA damage Gelmann and colleagues now show that the prostate cancer suppressor NKX3.1 plays a regulatory role in the prostate epithelial cell DNA damage response. NKX3.1 enhances the activity of the key DNA-damage-signaling kinase ataxia telangiectasia mutated (ATM) and, in turn, is an ATM substrate in a reaction leading to the downregulation of the NKX3.1 protein. These findings suggest a mechanism whereby partial loss of the haploinsufficient NKX3.1 protein can predispose to mutations, gene rearrangement, and prostate cancer.
http://linkinghub.elsevier.com/retrieve/pii/S2211124713003318