Introduction a t m a t R cs DNA p k c s 1 2 3 4 5 6 5 6 5 6 W i p 1 5 7 11 INK4a ARF 12 Discovery and initial characterization of Wip1 13 Wip1 13 Wip1 p53 13 14 1 1 13 15 Fig. 1 a top bottom b  Wip1 16 Wip1 17 16 Wip1 Wip1 16 Wip1 is a type 2C phosphatase 18 19 20 21 19 18 20 21 2+ 2+ 18 20 21 1 11 22 23 15 24 24 11 15 24 25 4 in vitro in vivo 2 7 9 26 Identification of Wip1 targets reveals it to be a homeostatic regulator of the DNA damage response Wip1 dephosphorylates DNA damage response/repair proteins at TXY motifs 1 1 7 26 27 30 31 Table 1 Identified Wip1 dephosphorylation targets Protein a Motif Kinase Protein function Wip1 effects p53 effect? Reference p38 MAPK T180 TXY MKK3/6 Stress response Dec. kinase activity Yes (dec.) 11 UNG2 T6 TXY ? Base excision repair Dec. uracil excision No 25 Chk1 S345 S/TQ ATR DNA damage response Dec. kinase activity Yes (dec.) 10 p53 S15 S/TQ ATM DNA damage response Dec. apoptosis Yes (dec.) 10 Chk2 b S/T/Q ATM DNA damage response Dec. kinase activity Yes (dec.) 9 ATM S1981 S/TQ c DNA damage response Dec. kinase activity Yes (dec.) 7 Mdm2 S395 S/TQ ATM p53 regulation Dec. p53 levels Yes (dec.) 8 a b c TXY motif: p38 11 32 33 28 34 35 11 11 TXY motif: UNG2 36 UNG 36 In vitro in vivo 25 37 25 25 38 Wip1 dephosphorylates DNA damage response proteins at S/TQ motifs S/TQ motif: Chk1, Chk2 39 40 41 42 43 44 45 46 47 48 10 In vitro In vivo 10 2 26 Fig. 2 Mdm2 Wip1 Wip1 circles octagons rectangles Small circles Black lines gray lines  in vitro in vivo 9 14 49 51 S/TQ motif: p53 52 p53 53 p53 54 55 56 in vitro 10 S/TQ motif: Mdm2 55 31 8 49 8 in vitro in vivo 8 2 S/TQ motif: ATM 4 Wip1 7 57 Wip1 is an oncogene 58 59 bona fide INK4A 17 60 Wip1 Wip1 Wip1 Wip1 Wip1 p53 Wip1 p53 Wip1 Mdm2 p53 61 Wip1 62 63 62 Wip1 Wip1 Wip1 63 Wip1 64 65 66 51 67 69 2 2 Wip1 p53 Wip1 p53 p53 Table 2 Human tumors with Wip1 gene amplification and/or overexpression Organ/Type DNA/RNA increase p53 mutation a Reference Breast adenocarcinoma b c 1/8   17   (16% CNG; ECG)     62   (11% CNG; ECG) 1/10 Poorer 64   d     65 Ovarian clear cell adenocarcinoma (40% CNG; ECG)   Poorer 66 Neuroblastoma (92% CNG; 28% O) 2/32 Poorer 67 Medulloblastoma (51% CNG; 88% O)   Poorer 70   (37% CNG; 27% O)     69 Gastric carcinoma (74% O)     53 Pancreatic adenocarcinoma (36% CNG)   Poorer 68 a b c d Wip1 17 60 p53 17 49 in vivo 70 Wip1 Wip1 Wip1 70 Mechanisms of Wip1 oncogenicity 17 49 60 70 2 p53 2 Wip1 Wip1 71 Wip1 Wip1 12 71 Wip1 12 Wip1 Wip1 INK4A ARF Wip1 Wip1 12 Wip1 Wip1 ARF INK4a Wip1 12 p53 p53 Wip1 p53 Wip1 Wip1 Wip1 ARF 12 12 Wip1 in vivo Wip1 Wip1 Wip1 Wip1 Wip1 Wip1 Wip1 INK4a Wip1 Wip1 Wip1 Wip1 57 Wip1 Wip1 Wip1 Wip1 Wip1 Wip1 Wip1 Wip1 14 Wip1 ARF Wip1 57 Wip1 49 Wip1 Wip1 Wip1 Wip1 Wip1 P Wip1 Wip1 Wip1 Wip1 49 Wip1 5 6 3 2 INK4a Table 3 Evidence that the Wip1 gene is an oncogene Evidence References 1. Wip1 specifically inhibits p53 signaling by multiple mechanisms 8 12 17 INK4A 12 3. Wip1 abrogates DNA damage response pathways and cell cycle checkpoints 10 25 51 4. Wip1 can transform primary rodent fibroblasts in conjunction with other oncogenes 17 51 62 5. Wip1 accelerates tumorigenesis in a mammary tumor susceptible model 72 6. Wip1 is amplified and overexpressed in multiple types of human tumors 17 62 64 71 7. Wip1 amplification and overexpression is often associated with poorer prognosis 64 66 67 68 70 8. Wip1 null primary embryo fibroblasts are resistant to transformation by oncogenes 12 9. Wip1 null mice are resistant to spontaneous and oncogene-induced tumors 12 51 59 Wip1 as a target for cancer chemotherapeutic approaches INK4A ARF 24 24 72 72 73 Other Wip1 biological functions Wip1 Wip1 71 74 Wip1 Wip1 Wip1 71 Wip1 75 Wip1 Wip1 p53 Conclusions, future prospects Wip1 Many important questions remain to be answered. The structure, catalytic activities and functional domains of Wip1 are still poorly understood. What does the C-terminal non-catalytic domain do? Are pTXpY and pS/pTQ the only target motifs recognized by Wip1 or are there others? And what are the other target proteins? The best guess is that there are likely to be hundreds of targets, if not more. Does Wip1 have other undiscovered functions? And perhaps most importantly, from a disease perspective, how many human cancers exhibit Wip1 overexpression, what are the mechanisms for Wip1-mediated oncogenesis, and how can our knowledge of these mechanisms assist us in designing novel therapies to fight cancer? The answers to these questions in the coming years should result in increased interest in this heretofore little studied protein.