Editors' ChoiceCancer

A New Partner for c-Myc

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Science's STKE  17 Jul 2007:
Vol. 2007, Issue 395, pp. tw254
DOI: 10.1126/stke.3952007tw254

For cells to become transformed (cancerous), critical cellular components that regulate cell growth must be disturbed. One way transformation can occur is if the activity of protein phosphatase 2A (PP2A), a serine and threonine phosphatase, is inhibited. PP2A functions as a heterotrimer of catalytic, regulatory, and scaffold proteins, splice variants and isoforms of which result in the formation of many different PP2A enzymes. PP2A dephosphorylates both the tumor suppressor protein p53 and the oncogenic transcription factor c-Myc. Thus far, studies of the tumor-suppressing activity of PP2A have not revealed the mechanisms of its inactivation in cancer. Junttila et al. therefore searched for binding partners with an epitope-tagged scaffolding subunit (PR65) of PP2A in HeLa cells (a transformed cell line derived from human cervical cancer cells). Immunoprecipitation studies followed by mass-spectrometric peptide sequencing identified a protein (called CIP2A for cancerous inhibitor of PP2A) that bound to PR65. Endogenous CIP2A coimmunoprecipitated with endogenous PP2A in HeLa cells, and both proteins were colocalized in the perinuclear region as demonstrated by confocal microscopy. Depletion of CIP2A in HeLa cells, using siRNA, decreased the abundance of c-Myc protein as measured by Western blotting (without affecting c-Myc mRNA) and decreased the proportion of c-Myc that was phosphorylated. In vitro phosphatase assays using immunoprecipitated c-Myc from control and CIP2A-specific siRNA-transfected cells showed that CIP2A inhibited PP2A-mediated dephosphorylation of c-Myc. Further immunoprecipitation studies showed that epitope-tagged CIP2A bound directly to the N terminus of epitope-tagged c-Myc. Injection of athymic mice with CIP2A-specific siRNA-expressing HeLa cells resulted in smaller tumors than were observed in mice injected with control HeLa cells. Overexpression of CIP2A in an immortalized, but not transformed, fibroblast cell line resulted in the formation of a greater number of foci (cell clusters) in soft agar (a characteristic of transformed cells) than were observed in control cells, demonstrating the oncogenic potential of CIP2A. Finally, the authors demonstrated the increased abundance of CIP2A mRNA and protein in transformed cell lines compared with normal cell lines and showed by immunohistochemistry an increased abundance of CIP2A in tissue from head-and-neck squamous cell carcinomas compared with that in normal tissue. As described in the accompanying review by Mumby, these data demonstrate for the first time a mechanism by which PP2A-mediated dephosphorylation of c-Myc is inhibited and characterize CIP2A as an oncogenic protein associated with human malignancies.

M. R. Junttila, P. Puustinen, M. Niemelä, R. Ahola, H. Arnold, T. Böttzauw, R. Ala-aho, C. Nielsen, J. Ivaska, Y. Taya, S.-L. Lu, S. Lin, E. K. L. Chan, X.-J. Wang, R. Grènman, J. Kast, T. Kallunki, R. Sears, V.-M. Kähäri, J. Westermarck, CIP2A inhibits PP2A in human malignancies. Cell 130, 51-62 (2007). [PubMed]

M. Mumby, PP2A: Unveiling a reluctant tumor suppressor. Cell 130, 21-24 (2007). [PubMed]

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