Targeting p27<sup>Kip1</sup>protein: its relevance in the therapy of human cancer

Borriello, Adriana; Bencivenga, Debora; Criscuolo, Maria; Caldarelli, Ilaria; Cucciolla, Valeria; Tramontano, Annunziata; Borgia, Alessia; Spina, Annamaria; Oliva, Adriana; Naviglio, Silvio; Ragione, Fulvio Della

doi:10.1517/14728222.2011.561318

Cited by 54 publications

(56 citation statements)

References 123 publications

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“…Additionally, it also performs cyclin-CDK-independent functions in apoptosis, cytoskeleton rearrangement and transcriptional regulation (Baldassarre et al, 2005;Timmerbeul et al, 2006;Wu et al, 2006;le Sage et al, 2007;Larrea et al, 2009;Belletti et al, 2010;Liu et al, 2010;See et al, 2010;Bhatia et al, 2010;Borriello et al, 2011;Fearon, 2011;Serres et al, 2011;Wander et al, 2011). However, different and sometimes contradictory findings have been reported about the role of p27 in the regulation of cell migration (Liu et al, 2010;See et al, 2010;Bhatia et al, 2010;Borriello et al, 2011;Fearon, 2011;Serres et al, 2011;Wander et al, 2011).…”

Section: Results P27mentioning

confidence: 99%

“…However, a growing body of evidence shows that the retention of p27 in the cytoplasm leads to the protein adopting an oncogenic role in the regulation of cytoskeletal dynamics and cell migration (Besson et al, 2004a;Besson et al, 2008). The exact function of cytoplasmic p27 is thus an active focus of several recent studies, but different and sometimes contradictory findings have been reported (Liu et al, 2010;See et al, 2010;Bhatia et al, 2010;Borriello et al, 2011;Fearon, 2011;Serres et al, 2011;Wander et al, 2011). In our current studies, we used time-lapse microscopy to monitor the random migration of p27 +/+ and p27 2/2 mouse embryonic fibroblasts (MEFs) in real time.…”

Section: Introductionmentioning

confidence: 99%

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Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

Zhang

Wang

Liang

et al. 2014

Journal of Cell Science

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Cell migration is a dynamic process that is central to a variety of physiological functions as well as disease pathogenesis. The modulation of cell migration by p27 has been reported, but the exact mechanism(s) whereby p27 intersects with downstream effectors that control cell migration have not been elucidated. By systematically comparing p27+/+ MEFs with genetically ablated p27−/− MEFs using wound healing, transwell and time-lapse microscopic analyses, we provide direct evidence demonstrating that p27 inhibits both directional and random cell migration. Identical results were obtained with normal and cancer epithelial cells using complementary knockdown and overexpression approaches. Additional studies revealed that overexpression of manganese superoxide dismutase (MnSOD) and reduced intracellular oxidation played a key role in increased cell migration in p27-deficient cells. Furthermore, we identified signal transducer and activator of transcription 3 (STAT3) as the transcription factor responsible for p27-regulated MnSOD expression which was further mediated by ERKs/ATF1-dependent transactivation of CRE within the stat3 promoter. Collectively, our data strongly indicate that p27 plays a crucially negative role in cell migration by inhibiting MnSOD expression in a STAT-3 dependent manner.

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Section: Results P27mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

Zhang

Wang

Liang

et al. 2014

Journal of Cell Science

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“…Two predominant mechanisms of dysregulation of p21 and p27 in cancer are altered subcellular localization and degradation. p57 is the least studied member of the Cip/Kip family, but its down-regulation both at the protein and transcriptional levels is associated with human malignancies, including liver, pancreatic, and colorectal cancers (reviewed by Borriello et al , 2011a ).…”

Section: Cip/kip Family Of Proteins and Cancermentioning

confidence: 99%

“…Here we review the basic properties of IDPs and then discuss the structural features and ' disorder-function ' relationships for two well characterized IDPs, the Cdk regulators p21 and p27. These IDPs play critical roles in regulating cell cycle progression and cell fate and are regarded as desirable drug targets against cancer (Funk and Galloway , 1998 ;Weiss , 2003 ;Borriello et al , 2011a ).…”

Section: Introduction: Intrinsically Disordered Proteins -A Distinct mentioning

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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“…Moreover, we observed synergistic apoptotic effects of SP2509 and PS against cultured and primary AML cells. This may be explained by greater induction of the levels of pro-apoptotic proteins p27 and BIM in AML cells exposed to co-treatment with SP2509 and PS, as compared to each drug alone (40,41). Previous reports have identified that LSD1-mediated histone demethylation triggers Myc-induced transcription, and the Myc 'core module' gene expression was altered in the leukemia stem cells in which LSD1 was knocked down (18,42).…”

Section: Sp2509 Is a Small Molecule Reversible Inhibitor Of Lsd1 (19)mentioning

confidence: 97%

Erratum: Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

Fiskus¹,

Sharma²,

Shah³

et al. 2017

Leukemia

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The histone demethylase LSD1 (KDM1A) demethylates mono-and di-methylated (Me2) lysine (K) 4 on histone H3. High LSD1 expression blocks differentiation and confers a poor prognosis in AML. Here, treatment with the novel LSD1 antagonist SP2509 attenuated the binding of LSD1 with the co-repressor CoREST, increased the permissive H3K4Me3 mark on the target gene promoters, and increased the levels of p21, p27 and C/EBPα in cultured AML cells. Additionally, SP2509 treatment or LSD1 shRNA inhibited the colony growth of AML cells. SP2509 also induced morphologic features of differentiation in the cultured and primary AML blasts. SP2509 induced more apoptosis of AML cells expressing mutant NPM1 than MLL fusion oncoproteins. Treatment with SP2509 alone significantly improved the survival of immune-depleted mice following tail-vein infusion and engraftment of cultured or primary human AML cells. Cotreatment with pan-HDAC inhibitor (HDI) panobinostat (PS) and SP2509 was synergistically lethal against cultured and primary AML blasts. Compared to each agent alone, co-treatment with SP2509 and PS significantly improved the survival of the mice engrafted with the human AML cells, without exhibiting any toxicity. Collectively, these findings show that the combination of LSD1 antagonist and pan-HDI is a promising therapy warranting further testing against AML. KeywordsKDM1A; histone deacetylase inhibitor; acute myeloid leukemia; differentiation Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use

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Targeting p27^Kip1protein: its relevance in the therapy of human cancer

Cited by 54 publications

References 123 publications

Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

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

Erratum: Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

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Targeting p27Kip1protein: its relevance in the therapy of human cancer

Cited by 54 publications

References 123 publications

Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

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

Erratum: Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

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Targeting p27^Kip1protein: its relevance in the therapy of human cancer