Inhibition of protein phosphatase 2A (PP2A) activity has been identified as a prerequisite for the transformation of human cells. However, the molecular mechanisms by which PP2A activity is inhibited in human cancers are currently unclear. In this study, we describe a cellular inhibitor of PP2A with oncogenic activity. The protein, designated Cancerous Inhibitor of PP2A (CIP2A), interacts directly with the oncogenic transcription factor c-Myc, inhibits PP2A activity toward c-Myc serine 62 (S62), and thereby prevents c-Myc proteolytic degradation. In addition to its function in c-Myc stabilization, CIP2A promotes anchorage-independent cell growth and in vivo tumor formation. The oncogenic activity of CIP2A is demonstrated by transformation of human cells by overexpression of CIP2A. Importantly, CIP2A is overexpressed in two common human malignancies, head and neck squamous cell carcinoma (HNSCC) and colon cancer. Thus, our data show that CIP2A is a human oncoprotein that inhibits PP2A and stabilizes c-Myc in human malignancies.
Senescence induction contributes to cancer therapy responses and is crucial for p53-mediated tumor suppression. However, whether p53 inactivation actively suppresses senescence induction has been unclear. Here, we show that E2F1 overexpression, due to p53 or p21 inactivation, promotes expression of human oncoprotein CIP2A, which in turn, by inhibiting PP2A activity, increases stabilizing serine 364 phosphorylation of E2F1. Several lines of evidence show that increased activity of E2F1-CIP2A feedback renders breast cancer cells resistant to senescence induction. Importantly, mammary tumorigenesis is impaired in a CIP2A-defi cient mouse model, and CIP2A-defi cient tumors display markers of senescence induction. Moreover, high CIP2A expression predicts for poor prognosis in a subgroup of patients with breast cancer treated with senescence-inducing chemotherapy. Together, these results implicate the E2F1-CIP2A feedback loop as a key determinant of breast cancer cell sensitivity to senescence induction. This feedback loop also constitutes a promising prosenescence target for therapy of cancers with an inactivated p53-p21 pathway. SIGNIFICANCE:It has been recently realized that most currently used chemotherapies exert their therapeutic effect at least partly by induction of terminal cell arrest, senescence. However, the mechanisms by which cell-intrinsic senescence sensitivity is determined are poorly understood. Results of this study identify the E2F1-CIP2A positive feedback loop as a key determinant of breast cancer cell sensitivity to senescence and growth arrest induction. Our data also indicate that this newly characterized interplay between 2 frequently overexpressed oncoproteins constitutes a promising prosenescence target for therapy of cancers with inactivated p53 and p21. Finally, these results may also facilitate novel stratifi cation strategies for selection of patients to receive senescence-inducing cancer therapies. Cancer Discov; 3(2);
Protein phosphatase 2A (PP2A) is a critical human tumor-suppressor complex. A recently characterized PP2A inhibitor protein, namely cancerous inhibitor of PP2A (CIP2A), has been found to be overexpressed at a high frequency in most of the human cancer types. However, our understanding of gene expression programs regulated by CIP2A is almost absent. Moreover, clinical relevance of the CIP2A-regulated transcriptome has not been addressed thus far. Here, we report a high-confidence transcriptional signature regulated by CIP2A. Bioinformatic pathway analysis of the CIP2A signature revealed that CIP2A regulates several MYC-dependent and MYCindependent gene programs. With regard to MYCindependent signaling, JNK2 expression and transwell migration were inhibited by CIP2A depletion, whereas MYC depletion did not affect either of these phenotypes. Instead, depletion of either CIP2A or MYC inhibited cancer cell colony growth with statistically indistinguishable efficiency. Moreover, CIP2A depletion was shown to regulate the expression of several established MYC target genes, out of which most were MYC-repressed genes. CIP2A small-interfering RNA-elicited inhibition of colony growth or activation of MYC-repressed genes was reversed at large by concomitant PP2A inhibition. Finally, the CIP2A signature was shown to cluster with basal-type and human epidermal growth factor receptor (HER)2-positive (HER2 þ ) breast cancer signatures. Accordingly, CIP2A protein expression was significantly associated with basal-like (P ¼ 0.0014) and HER2 þ (Po0.0001) breast cancers. CIP2A expression also associated with MYC gene amplification (Po0.001). Taken together, identification of CIP2A-driven transcriptional signature, and especially novel MYC-independent signaling programs regulated by CIP2A, provides important resource for understanding CIP2A's role as a clinically relevant human oncoprotein. With regard to MYC, these results both validate CIP2A's role in regulating MYC-mediated gene expression and provide a plausible novel explanation for the high MYC activity in basal-like and HER2 þ breast cancers.
Aimed at high loading and controlled release of oligonucleotides with short sequences of base-pairs, a novel series of mesoporous silica nanoparticles with three different pore sizes (3.5-5.0 nm) but the same cleavable surface linkers (MSN-Linker-Cys) were synthesized. The small particle size (∼70 nm) with radially aligned pore structure and the well-defined surface linkers terminated with amino groups led to unprecedentedly high adsorption capacities of a model oligo DNA (21 bp in length) into MSN-Linker-Cys particles, where MSN with a medium pore size of 4.5 nm exhibited the highest adsorption capacity (190 mg g(-1)). The electrostatic attraction forces between amino groups on the surfaces and phosphate groups of DNA led to N/P ratios less than 1 in the particles, and retained the loaded DNA molecules inside the particles albeit with some degree of premature release observed. Triggered by the presence of reducing agents mimicking those found inside cells, the disulfide bond was shown to be cleaved in the organic linkers, generating a thiol group terminated surface. As a consequence, the most efficient release of DNA was found for MSN-Linker-Cys at neutral pH. A sustained responsive release with lower premature release ratio was obtained after a PEG polymer was conjugated to the free amines on the particle surface post adsorption of DNA. This nanocarrier design was based on the understanding and tuning of the molecular interactions between oligonucleotides and the cationic linkers. Thus, it is expected to lay the possibility for the development of innovative and strategic approaches for advancing related gene delivery technology.
The graded expression of transcription factor interferon regulatory factor 4 (IRF4) regulates B cell development and is critical for plasma cell differentiation. However, the mechanisms, by which IRF4 elicits its crucial tasks, are largely unknown. To characterize the molecular targets of IRF4 in B cells, we established an IRF4-deficient DT40 B cell line. We found that in the absence of IRF4, the expression of several molecules involved in BCR signalling was altered. For example, the expression of B cell adaptor for PI3K (BCAP) was upregulated, whereas the SHIP (SH2-containing Inositol 5´-Phosphatase) expression was downregulated. These molecular unbalances were accompanied by increased BCR-induced calcium signalling, attenuated B cell linker protein (BLNK) and ERK activity and enhanced activity of PI3K/protein kinase B (Akt) pathway. Further, the IRF4-deficient cells showed dramatically diminished cytoskeletal responses to anti-IgM cross-linking. Our results show that IRF4 has an important role in the regulation of BCR signalling and help to shed light on the molecular mechanisms of B cell development and germinal centre response.
<p>Supplementary Figure 5 PDF file - 82K, Prognostic value of CIP2A in advanced human breast cancer patient material and characterization of vinorelbine effects</p>
<p>Supplementary Figure 4 PDF file - 269K, Characterization of hypomorphic CIP2A HOZ mice</p>
<p>Supplementary Table S1 PDF file - 71K, CIP2A overexpression frequencies and clinical relevance in human cancer types</p>
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