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| | Predicted modular structure of CIP2A. The indicated areas represent Armadillo repeats (Arm), leucine zipper (LZ) and coiled coil region. This prediction is based on programs superfamily 1.73 (Arm repeats), Prosite freq pat (leucine zipper) and Smart (coiled coil region). The phosphorylation sites have been identified in Daub et al., (2008) Mol Cell 31, 438-448, and the Ser904 has been reported also in Beausoleil et al., (2006) Nat Biotechnol 24, 1285-1292. Both studies analyzed peptides by mass spectrometry in high-throughput manner. |
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| Description | Translation: 905 amino acids.
Family: not defined. |
| Expression | Increased expression of CIP2A/KIAA1524 has been observed in various highly proliferating cancer cells. CIP2A is overexpressed in several types of human cancer tissues (gastric, breast, colon, squamous cell carcinomas of head and neck). Low expression of CIP2A/KIAA1524 is seen in most of the normal tissues, except in testis. CIP2A mRNA and protein expression is positively regulated by oncoprotein MYC whereas no change is seen in CIP2A expression in response to serum stimulation or during the cell cycle. A recent study demonstrated that Helicobacter pylori CagA-induced CIP2A expression is dependent on Src and MEK/ERK pathways. |
| Localisation | Cytoplasmic and perinuclear region. |
| Function | Human oncoprotein. Interacts with Protein Phosphatase 2A (PP2A) and inhibits PP2A-mediated dephosphorylation and subsequent proteolytic degradation of MYC protein. Inhibition of CIP2A expression by siRNA inhibits anchorage-independent growth of several types of human cancer cells. CIP2A inhibition also prevents tumor growth in mouse xenograft models. Two studies have shown that CIP2A siRNA induces expression of acidic b-galactoside indicating induction of cellular senescence. |
| Homology | CIP2A is well-conserved among mammalian species, sharing more than 90% identity. Vertebrates like Xenopus laevis (frog) and Danio rerio (bony fish) have homologs with 65% and 50% identity with human CIP2A respectively. Lower conservation of Cip2A is found throughout the animal kingdom. Nematostella vectensis (starfish) has a Cip2A homolog that has 39% identity with the human protein, but contains several deletions in the sequence, whereas Drosophila melanogaster (fly) homolog has a only 15% identity with human protein. |
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| Entity | Gastric cancer |
| Note | Several studies have shown CIP2A to be overexpressed in gastric cancer patients and cell lines (Soo Hoo et al., 2002; Li et al., 2008; Khanna et al., 2009). Furthermore, CIP2A depletion is shown to decrease proliferation, anchorage-independent growth, and expression of c-MYC protein in several gastric cancer cell lines (Khanna et al., 2009). CIP2A depletion also causes diminished clonogenic potential of tumor cells as well as induction of senescence in few gastric cancer cell lines (Li et al., 2008). Additionally, CIP2A and c-MYC immunopositivity associate in human gastric cancer specimens (Khanna et al., 2009). |
| Prognosis | Overexpression of CIP2A is associated with reduced overall survival in gastric cancer patients with tumour ≤ 5 cm, advanced stage (pT3-T4), and p53 immunopositivity. Moreover, association between CIP2A and markers of increased cellular malignancy (high SPF) further supports the role for CIP2A in promoting cancer progression (Khanna et al., 2009). |
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| Entity | Colon carcinoma |
| Note | CIP2A mRNA expression is shown to be overexpressed in colon cancer tissues compared to non-malignant tissue (Junttila et al., 2007). |
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| Entity | Head and neck squamous cell carcinoma (HNSCC) |
| Note | CIP2A mRNA and protein expression is shown to be overexpressed in human HNSCC cell lines. CIP2A immunopositivity in HNSCC tumor samples is restricted to tumour cells as stroma is mostly shown to be negative. Moreover, CIP2A is shown to promote c-MYC stability and malignant growth in NSCC cells. Additionally, role of CIP2A expression in HNSCC is analyzed using a mouse model of HNSCC wherein strong CIP2A immunopositivity is shown in both hyperplastic and HNSCC tissues in comparison to DMBA treated wild type mice (Junttila et al., 2007). |
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| Entity | Breast carcinoma |
| Note | CIP2A mRNA is not only shown to be overexpressed but also correlates with higher Scarff-Bloom-Richardson grades in samples from two independent human breast cancer patient cohorts. Furthermore, CIP2A mRNA expression positively correlated with lymph node positivity, expression of proliferations markers (Ki67) and p53 mutations in the tumor samples. Moreover, CIP2A protein expression was induced in mouse breast cancer mouse models presenting mammary gland-specific depletion of p53 and either BRCA1 or BRCA2. CIP2A depletion inhibits the expression of c-MYC, and anchorage-independent growth in breast cancer cells. Additionally, CIP2A is shown to support MDA-MB-231 xenograft growth in nude mice (Côme et al., 2009). |
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| Entity | Helicobacter pylori (H. pylori) infection |
| Note | H. pylori infection-induced CIP2A expression in cultured cells is dependent on CagA gene expression and CagA phosphorylation. Bacterial oncoprotein, CagA upregulates CIP2A expression and this upregulation is dependent on Src and MEK/ERK pathways. H. pylori infection-induced MYC stabilization is also shown to be partially reduced on CIP2A depletion (Zhao et al., 2009). |
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| A probability-based approach for high-throughput protein phosphorylation analysis and site localization. |
| Beausoleil SA, Villen J, Gerber SA, Rush J, Gygi SP. |
| Nat Biotechnol. 2006 Oct;24(10):1285-92. Epub 2006 Sep 10. |
| PMID 16964243 |
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| CIP2A is associated with human breast cancer aggressivity. |
| Come C, Laine A, Chanrion M, Edgren H, Mattila E, Liu X, Jonkers J, Ivaska J, Isola J, Darbon JM, Kallioniemi O, Thezenas S, Westermarck J. |
| Clin Cancer Res. 2009 Aug 15;15(16):5092-100. Epub 2009 Aug 11. |
| PMID 19671842 |
| |
| Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. |
| Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Korner R, Greff Z, Keri G, Stemmann O, Mann M. |
| Mol Cell. 2008 Aug 8;31(3):438-48. |
| PMID 18691976 |
| |
| Mechanisms of MYC stabilization in human malignancies. |
| Junttila MR, Westermarck J. |
| Cell Cycle. 2008 Mar 1;7(5):592-6. Epub 2007 Dec 29. (REVIEW) |
| PMID 18256542 |
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| MYC-dependent regulation and prognostic role of CIP2A in gastric cancer. |
| Khanna A, Bockelman C, Hemmes A, Junttila MR, Wiksten JP, Lundin M, Junnila S, Murphy DJ, Evan GI, Haglund C, Westermarck J, Ristimaki A. |
| J Natl Cancer Inst. 2009 Jun 3;101(11):793-805. Epub 2009 May 26. |
| PMID 19470954 |
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| CIP2A is overexpressed in gastric cancer and its depletion leads to impaired clonogenicity, senescence, or differentiation of tumor cells. |
| Li W, Ge Z, Liu C, Liu Z, Bjorkholm M, Jia J, Xu D. |
| Clin Cancer Res. 2008 Jun 15;14(12):3722-8. |
| PMID 18559589 |
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| PP2A: unveiling a reluctant tumor suppressor. |
| Mumby M. |
| Cell. 2007 Jul 13;130(1):21-4. (REVIEW) |
| PMID 17632053 |
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| Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. |
| Nagase T, Kikuno R, Ishikawa K, Hirosawa M, Ohara O. |
| DNA Res. 2000 Apr 28;7(2):143-50. |
| PMID 10819331 |
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| Preferential humoral immune response in prostate cancer to cellular proteins p90 and p62 in a panel of tumor-associated antigens. |
| Shi FD, Zhang JY, Liu D, Rearden A, Elliot M, Nachtsheim D, Daniels T, Casiano CA, Heeb MJ, Chan EK, Tan EM. |
| Prostate. 2005 May 15;63(3):252-8. |
| PMID 15538718 |
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| Cloning and characterization of a novel 90 kDa 'companion' auto-antigen of p62 overexpressed in cancer. |
| Soo Hoo L, Zhang JY, Chan EK. |
| Oncogene. 2002 Jul 25;21(32):5006-15. |
| PMID 12118381 |
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| Multiple pathways regulated by the tumor suppressor PP2A in transformation. |
| Westermarck J, Hahn WC. |
| Trends Mol Med. 2008 Apr;14(4):152-60. Epub 2008 Mar 10. (REVIEW) |
| PMID 18329957 |
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| Helicobacter pylori CagA upregulation of CIP2A is dependent on the Src and MEK/ERK pathways. |
| Zhao D, Liu Z, Ding J, Li W, Sun Y, Yu H, Zhou Y, Zeng J, Chen C, Jia J. |
| J Med Microbiol. 2010 Mar;59(Pt 3):259-65. Epub 2009 Dec 3. |
| PMID 19959630 |
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