p27Kip1: Regulation and Function of a Haploinsufficient Tumor Suppressor and Its Misregulation in Cancer

Philipp-Staheli, Jeannette; Payne, Shannon R.; Kemp, Christopher J.

doi:10.1006/excr.2000.5143

Cited by 266 publications

(228 citation statements)

References 200 publications

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“…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). Elucidation of the mechanisms of the FIR/SAP155 interaction promises to reveal the relation between c-myc expression, tumor progression, differentiation, and other signaling systems such as DNA-damage responses.…”

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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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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“…[8][9][10][11]13 In contrast, loss of or low expression of p27 Kip1 protein is associated with excessive cell proliferation and has been linked to many types of human tumors including breast and ovarian cancers. [40][41][42] Low levels of p27 Kip1 protein correlate well with higher-grade neoplasms and poor survival rates. [41][42] Thirdly, HER2 expression is inversely correlated with expression of p27 Kip1 protein in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…p27 Kip1 expression is known to be regulated at multiple levels: transcription, post-transcription, and noncovalent sequestration. 37,40,[50][51][52] Although transcriptional regulation and noncovalent sequestration may involve. 50-52 27 Kip1 protein is primarily regulated post-transcriptionally at the level of both protein translation and protein stability.…”

Section: Introductionmentioning

confidence: 99%

HER2-targeting Antibodies Modulate the Cyclin-dependent Kinase Inhibitor p27Kip1 via Multiple Signaling Pathways

Pruefer

Bast³

2004

Cell Cycle

129

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Anti-HER2 antibody trastuzumab is emerging as a frontline therapy for patients with metastatic breast cancers that overexpress HER2. Understanding the molecular mechanisms by which the antibody inhibits tumor growth should permit the design of even more effective trastuzumab-based protocols. Several groups including our own have demonstrated that induction of cyclin-dependent kinase (CDK) inhibitor p27 Kip1 protein is one of the key mechanisms of action of HER2-targeting antibodies. In this review, we discuss currently available data regarding the multiple signaling targets and pathways by which HER2-targeting antibodies upregulate p27 Kip1 protein in breast cancer cells that overexpress HER2. Anti-HER2 antibodies inhibit HER2-mediated signaling in cancer cells, ultimately upregulating the levels and activity of p27 Kip1 protein. At least six signaling targets and pathways are modulated by trastuzumab. By inhibiting CDK2 and decreasing Thr187 phosphorylation of p27 Kip1 , trastuzumab abrogates targeting of SCF-ubiquitin E3 ligase and minimizes proteasome degradation of p27 Kip1 . By inhibiting AKT and human kinase interacting stathmin (hKIS), trastuzumab blocks Thr157-, Thr198-and Ser10-induced p27 Kip1 translocation from the nucleus to the cytosol, which increases the inhibitory effect of p27 Kip1 . By inhibiting Jun activation domain-binding protein 1 (Jab1) trastuzumab increases nuclear retention of p27 Kip1 . By inhibiting cyclin D and c-Myc, trastuzumab releases the sequestrated p27b Kip1 protein from cyclin D-CDK4/6 complexes and increase the effect of p27 Kip1 on CDK2-cyclin E complexes. By stimulating minibrain related kinase (MIRK), trastuzumab stabilizes p27 Kip1 in the nucleus, which increases inhibitory action of p27 Kip1 on CDK2. The targets and pathways affected by trastuzumab work in concert to maximize the expression and inhibitory effect of p27 Kip1 , which leads to cell cycle G 1 arrest and growth inhibition.

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“…Moreover, p27 Kip1 is involved in many critical processes such as development, cell differentiation, cell death, and plays an important role in the development of many human neoplasms. 19,20 Downregulation of p27 Kip1 expression is a frequent event in human tumours 20 and is associated with poor prognosis in several malignancies like breast cancer. 21 In this regard, overexpression of p27 Kip1 via gene therapy might be a new possible treatment for human malignancies.…”

Section: Introductionmentioning

confidence: 99%

Intercellular trafficking and enhanced in vivo antitumour activity of a non-virally delivered P27-VP22 fusion protein

Zavaglia

Eymin

et al. 2003

Gene Ther

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VP22, a structural protein from herpes simplex virus type I, exhibits the unique property of intercellular trafficking. This protein is exported from primary expressing cells and subsequently imported into neighbouring cells. This property is conserved when VP22 is genetically fused to a protein, making it a promising tool to enhance the delivery of a gene product. We chose to study the intercellular transport and biological effect of a fusion protein between the putative tumour suppressor gene p27 Kip1 and VP22. We show that in vitro, P27VP22 is able to spread as efficiently as VP22. Functionality of the P27VP22 protein was demonstrated by its ability to inhibit cyclin/CDK2 complexes activity. In proliferation and clonogenicity assays, transfection with the P27VP22 plasmid resulted in a stronger cell growth inhibition when compared to transfection with the p27 Kip1 vector. In vivo, sub cutaneous tumours established in nude mice were injected with naked DNA encoding P27 or P27VP22. Our results show that P27VP22 can spread in vivo and that injections of the P27VP22 plasmid resulted in a significantly greater antitumour activity than injections of the P27 plasmid. This study confirms the usefulness of VP22-mediated delivery and suggests that P27VP22 may have applications in cancer gene therapy.

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p27Kip1: Regulation and Function of a Haploinsufficient Tumor Suppressor and Its Misregulation in Cancer

Cited by 266 publications

References 200 publications

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

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

HER2-targeting Antibodies Modulate the Cyclin-dependent Kinase Inhibitor p27Kip1 via Multiple Signaling Pathways

Intercellular trafficking and enhanced in vivo antitumour activity of a non-virally delivered P27-VP22 fusion protein

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