TABLE 3.
PLEIOTROPIC EFFECTS OF ATF3 REVEALED BY MOUSE MODELS THAT MODULATE THE EXPRESSION OF ATF3
| Ref. | |
|---|---|
| Gain-of-function | |
| Deleterious effects of ATF3 expression in various tissues | |
| Transgenic mice expressing ATF3 in the liver and pancreas (by the transthyrectin promoter) displayed liver dysfunction and defects in glucose homeostasis | 2,3 |
| Transgenic mice expressing ATF3 in the islets (by the PDX promoter) had small, abnormal islets and defects consistent with β-cell deficiency | 27 |
| Transgenic mice expressing ATF3 in the pancreatic β-cells (by the rat insulin promoter) had reduced β-cell mass and defects in glucose homeostasis | 39 |
| Transgenic mice expressing ATF3 in the heart (by the α-myosin heavy chain promoter) displayed conduction abnormalities and contractile dysfunction | 52 |
| Oncogenic effects of ATF3* | |
| Transgenic mice expressing ATF3 in the basal epithelial cells (by the bovine cytokeratin 5 promoter) developed epidermal hyperplasia, oral carcinoma, and mammary carcinomas (in biparous mice) | 66,67 |
| Ectopic expression of ATF3 in prostate cancer cells (AT2.1) increased their metastatic potential in a subcutaneous injection model using SCID mice | 4 |
| Ectopic expression of ATF3 in breast cancer cells (MCF10CA1a) increased their tumor initiation frequency as assayed by serial dilution combined with subcutaneous injection into nude mice | 73 |
| Ectopic expression of ATF3 in keratinocytes (HKC and SCC cells) reduced the expression of p53 and senescence-associated genes, and increased their tumorigenicity upon injection into the SCID mice | 70 |
| Ectopic expression of ATF3 in melanoma cells (B16F1) increased their lung colonization ability in an intravenous injection model using the syngeneic C57BL/6 mice | 30 |
| Antioncogenic effects of ATF3* | |
| Ectopic expression of ATF3 in colon cancer cells (HCT-116) reduced primary tumor growth in a subcutaneous injection model using nude mice | 8 |
| Loss-of-function | |
| Inhibition of overreactive inflammatory response in the organisms by ATF3 due to its immune suppression effects | |
| ATF3 KO mice demonstrated increased airway hyperresponsiveness and pulmonary inflammation in response to allergen | 17 |
| ATF3 KO mice demonstrated delayed recovery from an intranasal model of influenza A infection | 68 |
| ATF3 KO mice showed increased sensitivity to ventilator-induced lung injury | 1 |
| ATF3 KO mice displayed a hyperinflammatory response and rapidly succumb to death upon LPS-induced septic shock | 19 |
| Increased vulnerability of the organisms to infection by ATF3 due to its immune suppression effects | |
| ATF3 KO mice displayed decreased viral load in a MCMV infection model | 57 |
| Oncogenic effect of ATF3* | |
| Knockdown of ATF3 in Ras-transformed keratinocytes reduced the tumor-promoting effect of cyclosporin A, a calcineurin inhibitor | 70 |
| ATF3 antisense treatment of mice subcutaneously injected with colon cancer cells (HT29) resulted in reduced tumor growth and longer survival time | 29 |
| Antioncogenic effect of ATF3* | |
| Upon Ras transformation, immortalized ATF3 KO MEFs had enhanced tumorigenicity than the WT counterpart | 44 |
| Beneficial effects of ATF3 in the adaptation of β-cells to metabolic demands | |
| ATF3 KO mice displayed increased glucose intolerance upon high-fat diet feeding, presumably due to the decreased ability of their pancreatic β-cells to produce insulin and thus decreased ability to cope with higher metabolic demands | 75 |
See text for the criteria for inclusion. The consequences of ATF3 expression are pleiotropic; in addition, they may vary depending on the context of the cell types and stress models. MEF, mouse embryonic fibroblasts.
ATF3 can be either oncogenic or antioncogenic, depending on the models used. This dichotomy is reminiscent of the dichotomous roles of TGF-β in cancer development (11,46,56). Although the mechanisms behind the ATF3 dichotomy are not well understood, one potential mechanism is the degree of malignancy: in a pair of isogenic mammary epithelial cell lines, ATF3 enhances apoptosis in the untransformed cells, but protects the aggressive derivative cells from stress induced deleterious effects and enhances their cell motility and invasiveness in vitro (72).