Cancerous Inhibitor of Protein Phosphatase 2A, an Emerging Human Oncoprotein and a Potential Cancer Therapy Target

Khanna, Anchit; Pimanda, John E.; Westermarck, Jukka

doi:10.1158/0008-5472.can-13-1994

Cited by 136 publications

(168 citation statements)

References 30 publications

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“…This obviously requires that the identified interaction and its functional relevance are properly verified by subsequent experimentation or, as it is proposed here, filtered by RRP for their functional relevance. In the case of CIP2A, original identification was made from a single AP-MS purification yielding seven peptides with low Mascot score, and this has translated to over 100 publications establishing the protein as one of the most common cancer driver alterations across human cancers (5,36,37).…”

Section: Discussionmentioning

confidence: 99%

Relevance Rank Platform (RRP) for Functional Filtering of High Content Protein–Protein Interaction Data*

Pokharel

Saarela

Szwajda

et al. 2015

Molecular & Cellular Proteomics

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High content protein interaction screens have revolutionized our understanding of protein complex assembly. However, one of the major challenges in translation of high content protein interaction data is identification of those interactions that are functionally relevant for a particular biological question. To address this challenge, we developed a relevance ranking platform (RRP), which consist of modular functional and bioinformatic filters to provide relevance rank among the interactome proteins. We demonstrate the versatility of RRP to enable a systematic prioritization of the most relevant interaction partners from high content data, highlighted by the analysis of cancer relevant protein interactions for oncoproteins Pin1 and PME-1. We validated the importance of selected interactions by demonstration of PTOV1 and CSKN2B as novel regulators of Pin1 target c-Jun phosphorylation and reveal previously unknown interacting proteins that may mediate PME-1 effects via PP2A-inhibition. The RRP framework is modular and can be modified to answer versatile research problems depending on the nature of the biological question under study. Based on comparison of RRP to other existing filtering tools, the presented data indicate that RRP offers added value especially for the analysis of interacting proteins for which there is no sufficient prior knowledge available. Finally, we encourage the use of RRP in combination with either SAINT or CRAPome computational tools for selecting the candidate interactors that fulfill the both important requirements, functional relevance, and high confidence interaction detection. Molecular & Cellular

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Section: Discussionmentioning

confidence: 99%

Relevance Rank Platform (RRP) for Functional Filtering of High Content Protein–Protein Interaction Data*

Pokharel

Saarela

Szwajda

et al. 2015

Molecular & Cellular Proteomics

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“…However, despite RB proteins, the mechanisms by which E2F1 expression and activity are regulated during senescence regulation have been elusive. Recently, we demonstrated a previously unidentified positive feedback loop between E2F1 and another human oncoprotein CIP2A (43,44) and demonstrated that this feedback mechanism promotes tumorigenesis by suppressing senescence induction in breast cancer cell lines and in a HER2-driven breast cancer mouse model (17). Rescue experiments demonstrated that senescence induction either by p53 activation, or by direct adenoviral overexpression of p21, was fully dependent on the capacity of these stimuli to downregulate CIP2A expression (17).…”

Section: P21 Mediates P53-induced Senescencementioning

confidence: 95%

Molecular Pathways: Harnessing E2F1 Regulation for Prosenescence Therapy in p53-Defective Cancer Cells

Laine

Westermarck

2014

Clinical Cancer Research

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Induction of terminal proliferation arrest, senescence, is important for in vivo tumor-suppressive function of p53. Moreover, p53-mutant cells are highly resistant to senescence induction by either oncogenic signaling during cellular transformation or in response to different therapies. Senescence resistance in p53-mutant cells has been attributed mostly to inhibition of the checkpoint function of p53 in response to senescence-inducing stress signals. Here, we review very recent evidence that offers an alternative explanation for senescence resistance in p53-defective cancer cells: p21-mediated E2F1 expression. We discuss the potential relevance of these findings for senescence-inducing therapies and highlight cyclin-dependent kinases (CDK) and mechanisms downstream of retinoblastoma protein (RB) as prospective prosenescence therapeutic targets. In particular, we discuss recent findings indicating an important role for the E2F1-CIP2A feedback loop in causing senescence resistance in p53-compromised cancer cells. We further propose that targeting of the E2F1-CIP2A feedback loop could provide a prosenescence therapeutic approach that is effective in both p53-deficient and RB-deficient cancer cells, which together constitute the great majority of all cancer cells. Diagnostic evaluation of the described senescence resistance mechanisms in human tumors might also be informative for patient stratification for already existing therapies. Clin Cancer Res; 20(14); 3644-50. Ó2014 AACR.

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“…Importantly, despite a spermatogenesis defect, CIP2A is dispensable for normal mouse growth and development and the adult mice do not show any apparent pathology [19,20]. Consistent with the important role of PP2A in regulating various phosphorylationdependent pathways, CIP2A regulates phosphorylation and activity of many critical signaling proteins in cancer, including MYC, E2F1 and mTORC1-dependent growth signaling [15]. …”

mentioning

confidence: 69%

“…An endogenous PP2A inhibitor protein, cancerous inhibitor of PP2A (CIP2A), promotes malignant cell proliferation, and tumor growth in various cancer models [13][14][15][16]. Overexpression of CIP2A associates with poor patient prognosis and tumor aggressiveness in virtually all cancer types studied thus far, including breast cancer, prostate cancer, and oral HNSCC [14][15]17,18]. In HNSCC particularly, CIP2A seems to be essential for tumor growth as only around 50% of injections of CIP2A negative HNSCC cells resulted in xenograft tumor growth [13].…”

mentioning

confidence: 99%

CIP2A as a Potential Stratification Marker and Target for Tumor Responsiveness to DNA Damaging Therapies

Routila¹,

Westermarck²

2015

J Mol Biomark Diagn

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Head and neck squamous cell carcinoma; Radiation; Ovarian cancer; CHK1; Therapy response; Oct4; Cancer stem cell; CD24; CD44; MYC IntroductionDNA damaging therapies such as irradiation therapy and chemotherapy are used in the treatment of numerous cancer types both definitively and in combination with surgery. Cancer cells intrinsic resistance to DNA damaging therapies leads to failure in the successful eradication of cancer [1]. Mechanisms leading to DNA damage tolerance are inadequately known. It has been suggested, that there is a subpopulation of cancer cells, cancer stem cells, that would be responsible for the self-renewal potential of the tumor, and thus eventually, failed therapy response [2].Head and neck squamous cell carcinoma (HNSCC), the 6th most common cancer in the world, is treated with a combination of radiotherapy, radical surgery and platinum-based chemotherapeutics [3,4]. Recently, radiosensitization using EGFR inhibitors has challenged traditional chemotherapy [5]. While either radical surgery or definitive radiotherapy alone is often a sufficient treatment option for small local tumors, better loco regional control of more advanced disease is achieved with a combination of chemotherapeutics, surgery and irradiation [4]. Currently, there are no available biomarkers for the selection of suitable treatment modalities, which is thus solely based on patient characteristics and TNM staging of the cancer [6]. However, HNSCC has started to emerge as a set of cancers with very different behavioral patterns depending on tumor site, radiotolerance, carcinogen exposure, and stromal reaction [7][8][9]. These features and their clinical significance are as yet poorly characterized. Copious studies have lately aimed at identification of HNSCC subgroups for both prognostic and therapy stratification purposes [10]. Several potential biomarkers have been identified in HNSCC, but none of the studied biomarkers yet yield sufficient resolution to support their routine clinical use [6]. Promisingly, several clinical trials have recently been launched to study HPV infection as a predictive biomarker for reduced-intensity radiotherapy and EGFR inhibitor response in oropharyngeal HNSCC (ClinicalTrials.gov). The effect of HPV infection on prognosis of other HNSCC subclasses, however, is under debate [11]. Potential Role for CIP2A and Stem Cell Marker Oct4 as Cancer Patient Stratification Marker for DNA Damaging TherapiesUbiquitous protein phosphatase 2A (PP2A) complexes regulate serine/threonine phosphorylation of diverse cellular signaling pathways related to growth, cell viability, and malignant transformation [12]. An endogenous PP2A inhibitor protein, cancerous inhibitor of PP2A (CIP2A), promotes malignant cell proliferation, and tumor growth in various cancer models [13][14][15][16]. Overexpression of CIP2A associates with poor patient prognosis and tumor aggressiveness in virtually all cancer types studied thus far, including breast cancer, prostate cancer, and oral HNSCC [14][15]17,18]. In HNSCC particularly,...

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Cancerous Inhibitor of Protein Phosphatase 2A, an Emerging Human Oncoprotein and a Potential Cancer Therapy Target

Cited by 136 publications

References 30 publications

Relevance Rank Platform (RRP) for Functional Filtering of High Content Protein–Protein Interaction Data*

Relevance Rank Platform (RRP) for Functional Filtering of High Content Protein–Protein Interaction Data*

Molecular Pathways: Harnessing E2F1 Regulation for Prosenescence Therapy in p53-Defective Cancer Cells

CIP2A as a Potential Stratification Marker and Target for Tumor Responsiveness to DNA Damaging Therapies

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