PAK1IP1, a ribosomal stress-induced nucleolar protein, regulates cell proliferation via the p53-MDM2 loop

• Published in: Nucleic acids research Vol. 39; no. 6; pp. 2234 - 2248
• Main Authors: Yu, Weishi, Qiu, Zhongwei, Gao, Na, Wang, Liren, Cui, Hengxiang, Qian, Yu, Jiang, Li, Luo, Jian, Yi, Zhengfang, Lu, Hua, Li, Dali, Liu, Mingyao
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.03.2011
• Subjects: Amino Acid Sequence; Cell Cycle; Cell Line; Cell Nucleolus - chemistry; Cell Proliferation; DNA - biosynthesis; G1 Phase; Humans; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - metabolism; Intracellular Signaling Peptides and Proteins - physiology; Molecular Biology; Molecular Sequence Data; Nuclear Localization Signals; Nuclear Proteins - chemistry; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; Proto-Oncogene Proteins c-mdm2 - metabolism; Ribosomal Proteins - antagonists & inhibitors; Ribosomal Proteins - metabolism; Tumor Suppressor Protein p53 - metabolism; Ubiquitination
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkq1117

Cell growth and proliferation are tightly controlled via the regulation of the p53-MDM2 feedback loop in response to various cellular stresses. In this study, we identified a nucleolar protein called PAK1IP1 as another regulator of this loop. PAK1IP1 was induced when cells were treated with chemicals that disturb ribosome biogenesis. Overexpression of PAK1IP1 inhibited cell proliferation by inducing p53-dependent G1 cell-cycle arrest. PAK1IP1 bound to MDM2 and inhibited its ability to ubiquitinate and to degrade p53, consequently leading to the accumulation of p53 levels. Interestingly, knockdown of PAK1IP1 in cells also inhibited cell proliferation and induced p53-dependent G1 arrest. Deficiency of PAK1IP1 increased free ribosomal protein L5 and L11 which were required for PAK1IP1 depletion-induced p53 activation. Taken together, our results reveal that PAK1IP1 is a new nucleolar protein that is crucial for rRNA processing and plays a regulatory role in cell proliferation via the p53-MDM2 loop.