CIP2A
Protein CIP2A (Cancerous inhibitor of PP2A) (p90 autoantigen) [KIAA1524]
Publications[править]
Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis. CMA modulates proteomic organization through selective protein degradation, with targets including metabolic enzymes, cell growth regulators, and neurodegeneration-related proteins. CMA activity is low in [i]ad libitum[/i]-fed rodents but is increased by prolonged fasting. AKT negatively regulates CMA at the lysosomal membrane by phosphorylating and inhibiting the CMA regulator GFAP. We have previously reported that long-lived [i]Pou1f1/Pit1[/i] mutant (Snell) mice and [i]ghr[/i] (growth hormone receptor) knockout mice ([i]ghr[/i] KO) have lower AKT activity when fed compared to littermate controls, suggesting the hypothesis that these mice have increased baseline CMA activity. Here, we report that liver lysosomes from fed Snell dwarf mice and [i]ghr[/i] KO mice have decreased GFAP phosphorylation and increased CMA substrate uptake activity. Liver lysosomes isolated from fed Snell dwarf mice and [i]ghr[/i] KO mice injected with the protease inhibitor leupeptin had increased accumulation of endogenous CMA substrates, compared to littermate controls, suggesting an increase in CMA [i]in vivo[/i]. Mice with liver-specific ablation of GH (growth hormone) signaling did not have increased liver CMA, suggesting that a signaling effect resulting from a loss of growth hormone in another tissue causes enhanced CMA in Snell dwarf and [i]ghr[/i] KO mice. Finally, we find Snell dwarf mice have decreased protein levels (in liver and kidney) of CIP2A, a well-characterized CMA target protein, without an associated change in [i]Cip2a[/i] mRNA. Collectively, these data suggest that CMA is enhanced downstream of an endocrine change resulting from whole-body ablation of GH signaling. CMA: chaperone-mediated autophagy; GH: growth hormone; [i]ghr[/i] KO: growth hormone receptor knockout; LAMP2A: splice variant 1 of [i]Lamp2[/i] transcript; LC3-I: non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; Li[i]-ghr[/i] KO: liver-specific [i]ghr[/i] knockout; MA: macroautophagy; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; PBS: phosphate-buffered saline.
Keywords
- Aging
- chaperone-mediated autophagy
- endocrine control of autophagy
- endocrine signaling
- growth hormone
CIP2A is a recent identified oncogene that inhibits protein phosphatase 2A (PP2A) and stabilizes c-Myc in cancer cells. To investigate the potential oncogenic role and prognostic value of CIP2A, we comprehensively analyzed the CIP2A expression levels in pan-cancer and observed high expression level of CIP2A in majority cancer types, including hepatocellular carcinoma (HCC). Based on a validation cohort including 60 HCC and 20 non-tumorous tissue samples, we further confirmed the high mRNA and protein expression levels of CIP2A in HCC, and found high CIP2A mRNA expression level was associated with unfavorable overall and recurrence-free survival in patients with HCC. Mechanistic investigations revealed that inhibition of CIP2A significantly attenuated cellular proliferation in vitro and tumourigenicity in vivo. Bioinformatic analysis suggested that CIP2A might be involved in regulating cell cycle. Our experimental data further confirmed CIP2A knockdown induced cell cycle arrest at G1 phase. We found accumulated cellular senescence in HCC cells with CIP2A knockdown, companying expression changes of senescence associated proteins (p21, CDK2, CDK4, cyclin D1, MCM7 and FoxM1). Mechanistically, CIP2A knockdown repressed FoxM1 expression and induced FoxM1 dephosphorylation. Moreover, inhibition of PP2A by phosphatase inhibitor rescued the repression of FoxM1. Taken together, our results showed that CIP2A was highly expressed in HCC. Inhibition of CIP2A induced cell cycle arrest and promoted cellular senescence via repressing FoxM1 transcriptional activity, suggesting a potential anti-cancer target for patients with HCC.
MeSH Terms
- Autoantigens
- Biomarkers, Tumor
- Carcinoma, Hepatocellular
- Cell Cycle Checkpoints
- Cell Line, Tumor
- Cellular Senescence
- Disease Progression
- Forkhead Box Protein M1
- Gene Expression
- Gene Knockdown Techniques
- Hep G2 Cells
- Humans
- Intracellular Signaling Peptides and Proteins
- Liver Neoplasms
- Membrane Proteins
- Oncogenes
- Prognosis
- RNA, Messenger
- RNA, Neoplasm
Keywords
- CIP2A
- Cell cycle
- Cellular senescence
- FoxM1
- Hepatocellular carcinoma