Lessons from mouse models

Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein known to be mutated in endometrial cancer, inactivated in prostate cancer, and downregulated in several other cancers such as renal cell carcinoma, neuroblastoma, and pancreatic cancer. Par-4 downregulation is also associated with poor prognosis and recurrence in breast cancer. Expressed in all tissues and present in multiple cellular compartments, Par-4 protein shares homology of its key domains across human, mouse, and rat species. The most well-defined domains of Par-4 consist of two nuclear localization sequences in the N-terminal region (NLS1 and NLS2), a leucine zipper (LZ) domain at the C-terminus, and the effector SAC domain (Selective for Apoptosis in Cancer) naturally placed in the center of the molecule. Additionally, Par-4 and its effector domain can be secreted and found in the plasma of mice, normal individuals, and cancer patients. To better understand the function of Par-4 as a tumor suppressor, several groups have generated mouse models and studied the implications of deletion or overexpression of Par-4 in vivo. Par-4 loss in mice results in increased susceptibility to spontaneous tumors, as well as inducible tumors in various tissues. On the other hand, overexpression of Par-4 leads to longer cancer-free lifespan. Par-4 is also relevant outside the context of cancer as it promotes differentiation of T-cells toward the Th2 lineage in detriment of Th1, and Par-4 interacts with the dopamine receptor to ensure proper dopamine signaling. This chapter will discuss the most relevant studies utilizing mouse models that provide deeper insights into Par-4 function.