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PC4 is a post-transcriptional manipulator of D-type cyclins and centromere proteins

ABSTRACT: The cell cycle is an intensively control process, in which cell-cycle proteins display a cyclical expression pattern regulated by specific transcription, translation and degradation. Cell cycle progression is initiated by highly expressed D-type cyclins (D1/2/3) to facilitate DNA synthesis, subsequently driven by mitotic proteins formation (e.g., centromere proteins) that is responsible for mitosis onset. Whether there exist master regulators to keep the cycle rapidly “running” with D-type cyclins induction, as well as maintain the cycle in a stable process by centromere proteins modulation is of particular interest yet remains unclear at present. Here our study clarifies human positive cofactor 4 (PC4) as a previously unrecognized RNA binding protein (RBP), as a post-transcriptional master regulator to orchestrate CCND1 and CENPF expression. We reveal that lack of PC4 reduces CCND1 stability whereas enhances excessive CENPF translation, results in cell cycle arrest and mitotic defects. Furthermore, PC4 RNA binding activity is strictly controlled by S17 phosphorylation and K68 ubiquitination in a cell cycle-dependent way. Lastly, we use in vivo model to verify that PC4 deficiency amplifies response of cancer cells to CDK4/6 inhibitor, and PC4 induction accelerates liver regeneration after partial hepatectomy. These results highlight that cell-cycle gene expressions are dynamically and post-transcriptionally fine-tuned, and identify PC4 as an essential cell-cycle post-transcriptional manipulator that is profoundly applied within cancer and regeneration medicine.

INSTRUMENT(S): Thermo Scientific instrument model

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Liver

DISEASE(S): Liver Cancer

SUBMITTER: Qimei Pan

LAB HEAD: Chunmeng Shi

PROVIDER: PXD033637 | Pride | 2024-02-03

REPOSITORIES: Pride

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Project description:Phosphorylation is well-known in regulating various biological processes. However, comprehensively phosphoproteomic profiling in the termination of liver regeneration (LR) is still missing. Here, we used TMT labeling coupled with phosphopeptides enrichment and 2D LC-MS/MS analysis to establish a global phosphoproteomic map in mice liver at day 5 after partial hepatectomy. Altogether, 619 phosphorylation sites in 437 proteins were significantly up-regulated and 503 phosphorylation sites in 358 proteins were down-regulated. The differentially phosphorylated proteins were further classified according to their biological process, cellular components, molecular function and subcellular localization. KEGG pathway analysis showed that they mainly participate in metabolic pathways, DNA replication, tight junction and focal adhesion. Motif analysis of the identified phosphorylation sites has revealed a diverse array of consensus sequences, suggesting multiple kinase families such as MAPK, PKA/PKC, CaMK-II, CKII and CDK, may be involved in the termination of LR. Finally, several differentially phosphorylated proteins were validated by Co-immunoprecipitation and Western blot. Taken together, our data unravels the first comprehensive phosphoproteomic map in the termination of liver regeneration in mice, which greatly expands our knowledge in the complicate regulation of this process and provides new directions on the treatment of liver cancer using liver resection and donor liver transplantation. Biological significance: The novelty of this study is that we have established for the first time a global phosphoproteomic map in mice liver at day 5 after partial hepatectomy, which represents the termination of liver regeneration. Altogether, 9,775 phosphorylation sites in 3,458 proteins were identified, among which 7,738 phosphorylation site in 2,971 proteins were quantified. KEGG pathway analysis demonstrates markedly metabolic reprograming in termination of LR, which is further validated by selected validation of several differentially phosphorylated metabolic enzymes such as PDHA, ACACA and FASN. The consistent high phosphorylation of PDHA in the first 4 days and its rapidly decreased phosphorylation at day 5 after PH might be a key signal in controlling the switch between glycolysis and oxidative

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PC4 is a post-transcriptional manipulator of D-type cyclins and centromere proteins

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