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KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56a to initiate pancreatic cancer development

ABSTRACT: KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56a to initiate pancreatic cancer development

PROVIDER: PRJNA1052021 | ENA |

REPOSITORIES: ENA

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KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56a to initiate pancreatic cancer development [ATAC-seq]

Project description:Oncogenic mutations in KRAS are present in approximately 95% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are considered the initiating event during the development of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. While it is well established that KRAS mutations can drive the initiation of pancreatic oncogenesis, the effects of oncogenic KRAS signaling on regulation of phosphatases during this process is not fully appreciated. Protein Phosphatase 2A (PP2A) has been implicated in suppressing KRAS-driven cellular transformation. However, low PP2A activity is observed in PDAC cells compared to non-transformed cells, suggesting that suppression of PP2A activity is an important step in the overall development of PDAC. In the current study, we demonstrate that KRASG12D induces the expression of both Cancerous Inhibitor of PP2A (CIP2A), an endogenous inhibitor of PP2A activity, and the PP2A target, c-MYC. Consistent with these findings, KRASG12D sequestered the specific PP2A subunit responsible for c-MYC degradation, B56a, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiation in vivo, knockout of B56a promoted KRASG12D tumorigenesis by accelerating acinar-to-ductal metaplasia (ADM) and the formation of PanIN lesions. The process of ADM was attenuated ex vivo in response to pharmacological re-activation of PP2A utilizing direct small molecule activators of PP2A (SMAPs). Together, our results suggest that suppression of PP2A-B56a through KRAS signaling can promote Myc-driven initiation of pancreatic tumorigenesis.

2025-07-28 | GSE250099 | GEO

KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56a to initiate pancreatic cancer development [RNA-Seq]

2025-07-28 | GSE249867 | GEO

KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56a to initiate pancreatic cancer development [ATAC-seq]

Project description:KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56a to initiate pancreatic cancer development [ATAC-seq]

| PRJNA1052027 | ENA

KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56a to initiate pancreatic cancer development [RNA-Seq]

Project description:KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56a to initiate pancreatic cancer development [RNA-Seq]

| PRJNA1051059 | ENA

KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development.

Project description: Not available

| S-EPMC11142131 | biostudies-literature

KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development.

Project description: Not available

| S-EPMC12573297 | biostudies-literature

Structural mechanism for inhibition of PP2A-B56 and oncogenicity by CIP2A

Project description:Abstract The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56 is a human tumor suppressor. However, the molecular mechanisms inhibiting PP2A-B56in cancer are poorly understood. Here, we report molecular level details and structural mechanism of PP2A-B56inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56 trimer, CIP2A replaces PP2A-A subunit and thereby hijacks both the B56 and the catalytic PP2Ac subunit to form a CIP2A-B56-PP2Ac pseudotrimer. Further, CIP2A competes with B56 substrate binding by blocking the LxxIxE-motif substrate binding pocket on B56. Relevant to oncogenic activity of CIP2A across human cancers, the N-terminal head domain-mediated interaction with B56 stabilizes CIP2A protein. Functionally, CRISPR/Cas9-mediated single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation, and abrogated triple-negative breast cancer in vivo tumor growth. Collectively, we discover a unique multi-step “hijack and mute” mechanism of protein complex regulation inhibiting tumor suppressor PP2A-B56. Further, the results unfold single structural determinant for CIP2A´s oncogenic activity, potentially facilitating therapeutic modulation of CIP2A in cancer and other diseases.

2023-03-11 | PXD030297 | Pride

KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56a to initiate pancreatic cancer development

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-07-28 | GSE250101 | GEO

Cancerous inhibitor of PP2A (CIP2A) Constrains Th17 Differentiation by Modulating STAT3 Signaling

Project description:Genome-wide RNA seq data profile gene expression in human CIP2A silenced Th17 cells

2019-08-13 | GSE118094 | GEO

Cancerous inhibitor of PP2A (CIP2A) Constrains Th17 Differentiation by Modulating STAT3 Signaling

Project description:Cancerous inhibitor of PP2A (CIP2A) Constrains Th17 Differentiation by Modulating STAT3 Signaling

| PRJNA484395 | ENA