p27: A Barometer of Signaling Deregulation and Potential Predictor of Response to Targeted Therapies

Wander, Seth A.; Zhao, Dekuang; Slingerland, Joyce M.

doi:10.1158/1078-0432.ccr-10-0752

Cited by 158 publications

(182 citation statements)

References 90 publications

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“…In the study of ES cells, SSEA-3 + cells reportedly showed a faster cell cycle (24), and we further detected the decreased expression of cyclin-dependent kinase inhibitors p21 and p27 in SSEA-3 + cells. p27 is not only a cell cycle inhibitory factor of G1/S transition, but also a differentiation-promoting factor (27), and decreased expression of p27 in SSEA-3 + population has been reported in teratocarcinoma (28). p21 negatively regulates not only G1/S transition, but also G2/M transition (29), and its relation to SSEA-3 expression has not been reported.…”

Section: Discussionmentioning

confidence: 97%

SSEA-3 as a novel amplifying cancer cell surface marker in colorectal cancers

et al. 2012

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Abstract.Findings from studies on stem cells have been applied to cancer stem cell (CSC) research, but little is known about the relationship between ES cell-related cell surface markers and CSCs. In this study, we focused on stage-specific embryonic antigen 3 (SSEA-3), a marker of mesenchymal stem cells and Muse cells in colorectal cancer (CRC). Expression of SSEA-3 in human CRC cell lines and clinical specimens, specifically the relationship of SSEA-3 expression and the representative CSC markers (CD44, CD166, ALDH, CD24 and CD26) as well as with mesenchymal stem cell/Muse cell marker (CD105) were assessed. To characterize SSEA-3-expressing cells, tumorigenicity, sphere formation ability, expression of iPS genes (Oct4, NANOG, SOX2 and c-Myc), cell proliferation and cell cycle status were assessed. SSEA-3 expression was identified in Caco-2, DLD-1, HT-29, SW480 and HCT116, but not in CaR-1 cells. No significant relationship between SSEA-3 and other stem cell markers was detected. SSEA-3 + cells showed increased tumorigenicity in vivo, but lower sphere formation ability in vitro than SSEA-3 -. iPS gene expression was not correlated with SSEA-3 expression status. SSEA-3 + cells showed higher proliferative ability than SSEA-3 -through enhanced cell cycles by decreased expression of p21Cip1/Waf1 and p27 Kip1. Immunofluorescence analysis in clinical specimens indicated that expression of SSEA-3 is limited to stromal cells in normal mucosa but broad in poorly differentiated adenocarcinoma. These observations indicated that SSEA-3 + cells in CRC have immature phenotype but decreased self-renewal ability and may function as tumor transient amplifying cells or delayed contributing tumor-initiating cells.

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Section: Discussionmentioning

confidence: 97%

SSEA-3 as a novel amplifying cancer cell surface marker in colorectal cancers

et al. 2012

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“…c-Myc represses the transcription of key growth control and differentiation genes, including p21, p27, and growtharrest and DNA-damage proteins (23,24). In addition, p27 reportedly acts as a barometer for targeted therapies, because reduced p27 levels and p27 mislocalization have potential prognostic and therapeutic implications (25). However, under dysregulated conditions, as seen in cancer cells, the threshold for these checkpoints, such as DNA damage repair during cell cycle, is avoided because cell-cycle suppressors, such as the p21Cip1/p27 family of CDK inhibitors, are reduced (11,12,26,27).…”

Section: Discussionmentioning

confidence: 99%

Interactions between SAP155 and FUSE-Binding Protein-Interacting Repressor Bridges c-Myc and P27Kip1 Expression

Matsushita

Tamura

Tanaka

et al. 2013

Molecular Cancer Research

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Oncogenic c-Myc plays a critical role in cell proliferation, apoptosis, and tumorigenesis, but the precise mechanisms that drive this activity remain largely unknown. P27Kip1 (CDKN1B) arrests cells in G1, and SAP155 (SF3B1), a subunit of the essential splicing factor 3b (SF3b) subcomplex of the spliceosome, is required for proper P27 pre-mRNA splicing. FUSE-binding protein-interacting repressor (FIR), a splicing variant of PUF60 lacking exon5, is a c-Myc transcriptional target that suppresses the DNA helicase p89 (ERCC3) and is alternatively spliced in colorectal cancer lacking the transcriptional repression domain within exon 2 (FIRDexon2). FIR and FIRDexon2 form a homo-or hetero-dimer that complexes with SAP155. Our study indicates that the FIR/FIRDexon2/SAP155 interaction bridges c-Myc and P27 expression. Knockdown of FIR/FIRDexon2 or SAP155 reduced p27 expression, inhibited its pre-mRNA splicing, and reduced CDK2/ Cyclin E expression. Moreover, spliceostatin A, a natural SF3b inhibitor, markedly inhibited P27 expression by disrupting its pre-mRNA splicing and reduced CDK2/Cyclin E expression. The expression of P89, another FIR target, was increased in excised human colorectal cancer tissues. Knockdown of FIR reduced P89; however, the effects on P27 and P89 expression are not simply or directly related to altered FIR expression levels, indicating that the mechanical or physical interaction of the SAP155/FIR/FIRDexon2 complex is potentially essential for sustained expression of both P89 and P27. Together, the interaction between SAP155 and FIR/ FIRDexon2 not only integrates cell-cycle progression and c-Myc transcription by modifying P27 and P89 expression but also suggests that the interaction is a potential target for cancer screening and treatment. Mol Cancer Res; 11(7); 689-98. Ó2013 AACR.

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“…Cytoplasmic p27-dependent promotion of cell migration was later shown by others to be due to direct interaction with the Rho GTPase, RhoA, and inhibition of its interactions with guanine nucleotide exchange factors (GEFs), which promote RhoA activation (Besson et al , 2004 ). This regulatory mechanism has been shown to contribute to tumor invasion and progression (Larrea et al , 2009b ) and is also thought to mediate tumor metastasis (Wander et al , 2011 ). Recently, it was shown that phosphorylation of p27 on Thr198, in this case by the kinase RSK1, was also associated with cytoplasmic localization and RhoA-dependent promotion of cell migration (Larrea et al , 2009a ).…”

Section: Cip/kip Family Of Proteins and Cancermentioning

confidence: 99%

Disorder-function relationships for the cell cycle regulatory proteins p21 and p27

Mitrea

Yoon²,

Ou³

et al. 2012

BCHM

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The classic structure-function paradigm has been challenged by a recently identifi ed class of proteins: intrinsically disordered proteins (IDPs). Despite their lack of stable secondary or tertiary structure, IDPs are prevalent in all forms of life and perform myriad cellular functions, including signaling and regulation. Importantly, disruption of IDP homeostasis is associated with numerous human diseases, including cancer and neurodegeneration. Despite wide recognition of IDPs, the molecular mechanisms underlying their functions are not fully understood. Here we review the structural features and disorder-function relationships for p21 and p27, two cyclindependent kinase (Cdk) regulators involved in controlling cell division and fate. Studies of p21 bound to Cdk2/cyclin A revealed that a helix stretching mechanism mediates binding promiscuity. Further, investigations of Tyr88-phosphorylated p27 identifi ed a signaling conduit that controls cell division and is disrupted in certain cancers. These mechanisms rely upon a balance between nascent structure in the free state, induced folding upon binding, and persistent fl exibility within functional complexes. Although these disorder-function relationships are likely to be recapitulated in other IDPs, it is also likely that the vocabulary of their mechanisms is much more extensive than is currently understood. Further study of the physical properties of IDPs and elucidation of their links with function are needed to fully understand the mechanistic language of IDPs.

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p27: A Barometer of Signaling Deregulation and Potential Predictor of Response to Targeted Therapies

Cited by 158 publications

References 90 publications

SSEA-3 as a novel amplifying cancer cell surface marker in colorectal cancers

SSEA-3 as a novel amplifying cancer cell surface marker in colorectal cancers

Interactions between SAP155 and FUSE-Binding Protein-Interacting Repressor Bridges c-Myc and P27Kip1 Expression

Disorder-function relationships for the cell cycle regulatory proteins p21 and p27

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