Phosphorylation-Dependent Stabilization of Collaborator of ARF (CARF) Suppresses Lymphoma Cell Proliferation.

Abstract

Uncontrolled cell proliferation drives tumorigenesis and malignant progression, making cell cycle regulation a promising strategy for cancer therapy. Phosphorylation plays pivotal roles in cancer initiation and metastasis by regulating the cancer-related proteins. Identifying key phosphorylation sites is essential for inhibiting tumor cell proliferation and optimizing therapy strategy. Here, this study reveals the strong association of oncogene Collaborator of ARF (CARF), a cell-division regulator interacting with p53, with prognosis and survival of lymphoma patients through pan-cancer analysis. In addition, this study finds that mammalian CARF shares homology with Kip-Related Protein6 (KRP6), a cell cycle inhibitor from higher plant Arabidopsis. KRP6 is regulated by casein kinase1 via phosphorylation at serines 75 and 109, which are conservative in CARF at serines 316 and 356. Systemic assays conducted with various B-cell lymphoma cell lines and a mouse xenograft model demonstrate that the non-phosphorylation variant of CARF inhibited cell proliferation and lymphoma formation more effectively than wild-type CARF, highlighting the crucial regulatory role of phosphorylation at these conserved sites in controlling B-cell lymphoma cell proliferation. A similar suppressive effect is observed with plant KRP6, suggesting a cross-species bioengineering application. These findings enlighten the application of phosphorylation-modified proteins as therapeutic targets in precise lymphoma treatments.