PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “p27”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed1997

High level expression of p27(kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27(kip1) and degree of malignancy in human breast and colorectal cancers.

The expression of cyclin-dependent kinase inhibitor p27(kip1) in human tumors and normal tissues was investigated using a panel of novel anti-p27(kip1) mAbs. An inverse correlation between expression of p27(kip1) and cell proliferation was generally observed after analyzing its expression in 25 different normal human tissues. In some highly proliferative human breast cancer cells, however, high level p27(kip1) expression was seen, indicating the existence of a mechanism by which some growing tumor cells may tolerate this inhibitor of cell cycle progression. Detailed studies demonstrated a correlation between the high level expression of p27(kip1) and cyclin D1 in human breast cancer cells. There was also an inverse correlation between the expression of p27(kip1) and the degree of tumor malignancy in human breast and colorectal cancers, indicating that p27(kip1) may be a useful prognostic marker in these cancers.

Biomarkers, Tumor↗
PubMed2002

Rho activity can alter the translation of p27 mRNA and is important for RasV12-induced transformation in a manner dependent on p27 status.

The amount of p27(Kip1) establishes a threshold to which G(1) cyclin-cyclin-dependent kinase complexes must surpass prior to cells progressing into S-phase. The amount of p27 is greatest in G(0) cells, intermediate in G(1) cells, and lowest in S-phase cells. However, there is little known regarding the pathways and mechanisms controlling p27 accumulation in G(0) cells. We report that inhibition of Rho, by either lovastatin or C3 exoenzyme, can increase the translational efficiency of p27 mRNA. Similar pharmacologic inhibition of the phosphatidylinositol 3-kinase, the S6 kinase, and the Mek1 kinase pathways all fail to increase translational efficiency in MDA468 cells. This Rho-responsive element lies within a 300-nucleotide region at the 3'-end of the mRNA. By supporting the significance of this signaling pathway to Rho function, we showed that the suppression of Ras(V12) transformation by RhoA(N19) is blocked in p27-/- cells. In contrast this activity is not blocked in Rb-/- or p16-/- cells. The resistance of p27-/- cells to RhoA(N19) is not associated with a failure of RhoA(N19) to accumulate to amounts sufficient to block Rho activity as measured by the organization of actin stress fibers. Together these results indicate a link between Rho and p27.

3' Untranslated Regions↗
PubMed2002

Pituitary hyperplasia in glycoprotein hormone alpha subunit-, p18(INK4C)-, and p27(kip-1)-null mice: analysis of proteins influencing p27(kip-1) ubiquitin degradation.

Most spontaneously developing hyperplastic and neoplastic lesions of the pituitary occur in the anterior pituitary. Targeted disruption of various cell-cycle proteins, including Rb, p27(kip1) (p27), and p18(INK4c) (p18), is associated with intermediate lobe pituitary hyperplasia. To develop a model of anterior pituitary proliferation to study the pathogenesis of pituitary tumors, we crossed the glycoprotein hormone alpha-subunit (alphaSU)-null mice that develop thyroid-stimulating hormone (TSH) cell hyperplasia with p18-null mice. The resulting offsprings developed accelerated enlargement of the anterior lobe with predominantly TSH cell hyperplasia. Immunohistochemical and histological analyses of these mice along with p27/p18 double-null mice, p18-null mice, and p27-null mice showed evidence of TSH, adrenocorticotropic hormone, prolactin, and luteinizing hormone hyperplasia. To determine whether there were alterations of p27 and the target proteins implicated in the ubiquitin degradation of p27 and other cyclin-dependent kinase inhibitors, we examined expression of SKP 2, Grb 2, and Jab 1 in the pituitaries of null mice. In the alphaSU-null mice there were decreased levels of SKP 2 and elevated levels of Grb 2 expression by Western blot analysis. Immunohistochemical analysis of the pituitary showed elevated Grb 2 in alphaSU-null and p18/alphaSU double-null mice. Jab 1 levels were not different from controls in the pituitary. These results show that 1) the p18/alphaSU double-null mice represent a good model to study the rapid development of anterior pituitary hyperplasia, and 2) various proteins important in p27 and other cyclin-dependent kinase inhibitor protein degradation are altered in the pituitary of alphaSU-null and p18/alphaSU double-null mouse models.

Animals↗
PubMed2003

Regulatory role of PI 3-kinase on expression of Cdk4 and p27, nuclear localization of Cdk4, and phosphorylation of p27 in corneal endothelial cells.

PURPOSE: FGF-2 is a potent mitogen of rabbit corneal endothelial cells (CECs). This study was undertaken to investigate whether PI 3-kinase participates in cell cycle regulation in response to stimulation with FGF-2 in CECs. METHODS: Cell proliferation was assayed by counting the cells. Subcellular localization of proteins was determined by immunofluorescent staining and expression of cyclin-dependent kinase 4 (Cdk4), p27(Kip1) (p27), phosphatidylinositol 3 (PI 3)-kinase, protein kinase B/Akt (Akt), and beta-actin was analyzed by immunoblot. PI 3-kinase activity was determined by measuring production of phosphatidylinositol-3-phosphate. LY294002 was used to inhibit PI 3-kinase. RESULTS: CEC required prolonged and continuous exposure to FGF-2. FGF-2 at 10 ng/mL markedly stimulated PI 3-kinase enzyme activity, and stimulation with FGF-2 also caused activation of Akt. LY294002 inhibited both cell proliferation and PI 3-kinase activity in a concentration-dependent manner. The role of PI 3-kinase in cell cycle stimulation was determined: FGF-2 markedly upregulated expression of Cdk4 and stimulated translocation of Cdk4 into nuclei, whereas LY294002 markedly blocked upregulation of Cdk4 expression, and the inhibitor facilitated nuclear export of Cdk4. In contrast, FGF-2 significantly downregulated expression of p27 and facilitated phosphorylation of p27. LY294002 completely blocked the action of FGF-2 on the expression and phosphorylation of p27. CONCLUSIONS: These data indicate that PI 3-kinase ultimately leads to activation of the cell cycle machinery in response to FGF-2. It does so by upregulating expression of Cdk4, facilitating the nuclear import of Cdk4, and sequestering Cdk4 in the nuclei as it simultaneously downregulates expression of p27 and facilitates the proteolysis of the molecule by phosphorylation.

Actins↗
PubMed1988

Isolation of a variant endogenous avian leukosis virus: non-productive exogenous infection with endogenous viruses containing p27 and p27(0).

Ten replication-competent endogenous avian leukosis viruses (ALVs) with subgroup E specificity were isolated from six commercial chicken lines of mixed breed. All the ALVs isolated belonged to a variant class of endogenous viruses with a major group-specific antigen, p27, identical in size to that of exogenous viruses and different from the p27 degrees of endogenous viruses isolated from White Leghorn chickens. It was possible to infect chickens exogenously with endogenous viruses (containing p27) and with Rous-associated virus type 0 (containing p27 degrees) but infection was non-productive. Congenital transmission and shedding did not occur in chickens infected with endogenous viruses containing p27 degrees or in chickens infected with endogenous viruses containing p27. Restriction of endogenous virus replication in some tissues (heart, spleen and meconia) of viraemic chickens was observed suggesting that exogenous infection of chickens with endogenous viruses differs from an infection with exogenous ALVs.

Animals↗
PubMed1999

Expression of p27(kip) and other cell cycle regulators in malignant peripheral nerve sheath tumors and neurofibromas: the emerging role of p27(kip) in malignant transformation of neurofibromas.

There is little information regarding the status of cell cycle regulators in malignant peripheral nerve sheath tumors (MPNSTs) and neurofibromas (NFs). In this study, we investigated patterns of expression of p53 and pRB, cyclin-dependent kinase inhibitors (CKIs) p21 and p27, as well as cyclins D1 and E, in a cohort of 35 well-characterized MPNSTs and 16 NFs. These phenotypes were correlated with proliferative index, as assessed by Ki-67, as well as clinicopathological parameters of poor outcome. p53 nuclear overexpression was found in 10 of 35 (29%) MPNSTs, and it was lacking in NFs (P = 0.02). There were no differences in the patterns of expression of pRB, cyclin D1, and p21 between MPNSTs and NFs. However, p27 nuclear expression was present in most NFs, but it was absent in the majority of MPNSTs, which displayed cytoplasmic staining (P < 0.001). Nuclear cyclin E expression was more pronounced in MPNSTs than in NFs. We observed inverse patterns of expression for nuclear p27 and nuclear cyclin E expression. The staining profiles of cytoplasmic p27 and nuclear cyclin E expression were found to be statistically associated (P = 0.01). High Ki-67 expression was found in 20 of 34 (59%) MPNSTs but was absent in NFs (P < 0.001). Furthermore, detection of cytoplasmic p27 expression was found to be a prognostic factor for poor survival in MPNSTs (P = 0.03, relative risk = 2.4).

Cell Cycle↗
PubMed1983

Monoclonal antibodies to three epitopic regions of feline leukemia virus p27 and their use in enzyme-linked immunosorbent assay of p27.

Three different monoclonal antibodies were developed against the major core protein (p27) of feline leukemia virus (FeLV). Each antibody was directed against a different epitope of the species-specific portion of FeLV-p27. The 3 antibodies reacted with 5 different isolates of FeLV but not with 7 other retroviruses (MuLV (Rauscher), MuLV (AKR), MPMV, MMTV, SMRV, BAEV, RD 114). These monoclonal antibodies could readily be adapted to an enzyme-linked immunosorbent assay (ELISA) for the specific measurement of FeLV-p27. When compared in an ELISA with conventional reagents, the battery of monoclonal antibodies proved to be as sensitive as conventional polyclonal antibodies.

Animals↗
PubMed2003

The lack of cyclin kinase inhibitor p27(Kip1) ameliorates progression of diabetic nephropathy.

Cyclin kinase inhibitor p27(Kip(1)) (p27) has been shown to be upregulated in glomeruli of diabetic animals and mesangial cells cultured under high glucose. This study was an investigation of the role of p27 in the progression of diabetic nephropathy. Mice deficient in p27 (p27 -/-) and wild-type mice (p27 +/+) were studied 12 wk after diabetes induction by streptozotocin. Blood glucose and BP were comparable between diabetic p27 +/+ and p27 -/- mice. The kidney weight to body weight ratio and glomerular volume increased in diabetic p27 +/+ mice. In contrast, these parameters did not change in diabetic p27 -/- mice. Similarly, albuminuria developed in diabetic p27 +/+ mice but not in diabetic p27 -/- mice. The mesangial expansion was significantly milder in diabetic p27 -/- mice than that in diabetic p27 +/+ mice. These changes were associated with a similar increase in glomerular TGF-beta expression in diabetic p27 +/+ and p27 -/- mice. However, glomerular protein expression of fibronectin, a target of TGF-beta, increased only in diabetic p27 +/+ mice. In mesangial cells cultured from p27 +/+ mice, exposure to high glucose caused significant increases in total protein content and [(3)H]-leucine incorporation. On the other hand, high glucose caused a significant reduction in these parameters in cells from p27 -/- mice. Phosphorylation of 4E-BP1, the translation inhibitor, increased after exposure to high glucose in p27 +/+ cells. In p27 -/- cells, the level of phosphorylated 4E-BP1 was higher than that in control p27 +/+ cells and decreased under high glucose conditions. In conclusion, renal hypertrophy, glomerular hypertrophy, and albuminuria did not develop, and mesangial expansion was milder in diabetic p27 -/- mice despite glomerular TGF-beta upregulation. These results suggest that controlling p27 function may ameliorate diabetic nephropathy.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation.

The cellular abundance of the cyclin-dependent kinase (Cdk) inhibitor p27 is regulated by the ubiquitin-proteasome system. Activation of p27 degradation is seen in proliferating cells and in many types of aggressive human carcinomas. p27 can be phosphorylated on threonine 187 by Cdks, and cyclin E/Cdk2 overexpression can stimulate the degradation of wild-type p27, but not of a threonine 187-to-alanine p27 mutant [p27(T187A)]. However, whether threonine 187 phosphorylation stimulates p27 degradation through the ubiquitin-proteasome system or an alternative pathway is still not known. Here, we demonstrate that p27 ubiquitination (as assayed in vivo and in an in vitro reconstituted system) is cell-cycle regulated and that Cdk activity is required for the in vitro ubiquitination of p27. Furthermore, ubiquitination of wild-type p27, but not of p27(T187A), can occur in G1-enriched extracts only upon addition of cyclin E/Cdk2 or cyclin A/Cdk2. Using a phosphothreonine 187 site-specific antibody for p27, we show that threonine 187 phosphorylation of p27 is also cell-cycle dependent, being present in proliferating cells but undetectable in G1 cells. Finally, we show that in addition to threonine 187 phosphorylation, efficient p27 ubiquitination requires formation of a trimeric complex with the cyclin and Cdk subunits. In fact, cyclin B/Cdk1 which can phosphorylate p27 efficiently, but cannot form a stable complex with it, is unable to stimulate p27 ubiquitination by G1 extracts. Furthermore, another p27 mutant [p27(CK-)] that can be phosphorylated by cyclin E/Cdk2 but cannot bind this kinase complex, is refractory to ubiquitination. Thus throughout the cell cycle, both phosphorylation and trimeric complex formation act as signals for the ubiquitination of a Cdk inhibitor.

Cell Cycle↗
PubMed2002

Expression of phosphorylated p27(Kip1) protein and Jun activation domain-binding protein 1 in human pituitary tumors.

The cyclin-dependent kinase inhibitor p27(Kip1) (p27) plays a pivotal role in controlling cell proliferation during development and tumorigenesis. p27 has been implicated in pituitary tumorigenesis in studies of knockout mice and in analyses of human pituitary tumor samples. In this study, we further explored the role of p27 in human pituitary tumors by measuring levels of phosphorylated p27 (P-p27), and also Jun activation domain-binding protein 1 (Jab1), which is thought to facilitate the phosphorylation and degradation of p27, in normal pituitary tissue (n = 21), pituitary adenomas (n = 75), and pituitary carcinomas (n = 10). The amount of p27 protein in corticotroph adenomas and pituitary carcinomas was much lower than that in normal pituitary tissue or other types of pituitary adenoma. Nuclear P-p27 protein levels were significantly decreased in the adenomas, compared with the normals, and were much lower in the carcinomas, compared with either normal pituitary tissue or pituitary adenomas. However, P-p27 levels in corticotroph adenomas were similar to normal pituitary tissue, thus demonstrating a greatly increased ratio of P-p27 to p27 specifically in corticotroph tumors. No difference was found in Jab1 protein levels in either corticotroph tumors or other pituitary adenomas, compared with normal tissue, but there was a small but significant increase in Jab1 levels in carcinomas. Corticotroph and metastatic tumors both showed a significantly higher Ki-67 labeling index than normal pituitary or other types of pituitary adenomas, and in general the Ki-67 labeling index was negatively correlated with p27 nuclear staining. The amount of p27 and Jab1 mRNA was positively correlated in all pituitary samples studied but did not correlate with the changes in immunostaining. Our findings suggest that in corticotroph tumors there is an accentuated phosphorylation of p27 into P-p27, possibly related to increased cyclin E expression, whereas both p27 and P-p27 are subject to increased degradation in pituitary carcinomas. Such variations in phosphorylation may play a role in pituitary tumorigenesis, but modulation of Jab1 is unlikely to be important in the pathogenesis of pituitary adenomas.

Adenoma↗
PubMed1995

Redistribution of the CDK inhibitor p27 between different cyclin.CDK complexes in the mouse fibroblast cell cycle and in cells arrested with lovastatin or ultraviolet irradiation.

The cyclin-dependent kinase (CDK) inhibitor p27 binds and inhibits the kinase activity of several CDKs. Here we report an analysis of the behavior and partners of p27 in Swiss 3T3 mouse fibroblasts during normal mitotic cell cycle progression, as well as in cells arrested at different stages in the cycle by growth factor deprivation, lovastatin treatment, or ultraviolet (UV) irradiation. We found that the level of p27 is elevated in cells arrested in G0 by growth factor deprivation or contact inhibition. In G0, p27 was predominantly monomeric, although some portion was associated with residual cyclin A.Cdk2. During G1, all of p27 was associated with cyclin D1.Cdk4 and was then redistributed to cyclin A.Cdk2 as cells entered S phase. The loss of the monomeric p27 pool as cyclins accumulate in G1 is consistent with the in vivo and in vitro data showing that p27 binds better to cyclin.CDK complexes than to monomeric CDKs. In growing cells, the majority of p27 was associated with cyclin D1 and the level of p27 was significantly lower than the level of cyclin D1. In cells arrested in G1 with lovastatin, cyclin D1 was degraded and p27 was redistributed to cyclin A.Cdk2. In contrast to p21 (which is a p27-related CDK inhibitor and is induced by UV irradiation), the level of p27 was reduced after UV irradiation, but because cyclin D1 was degraded more rapidly than p27, there was a transient increase in binding of p27 to cyclin A.Cdk2. These data suggest that cyclin D1.Cdk4 acts as a reservoir for p27, and p27 is redistributed from cyclin D1.Cdk4 to cyclin A.Cdk2 complexes during S phase, or when cells are arrested by growth factor deprivation, lovastatin treatment, or UV irradiation. It is likely that a similar principle of redistribution of p27 is used by the cell in other instances of cell cycle arrest.

3T3 Cells↗
PubMed2003

[Impact of cyclin-dependent kinase inhibitor p27 on resistance of ovarian cancer multicellular spheroids to taxol].

OBJECTIVE: To examine the expression of the cyclin-dependent kinase inhibitor p27 in ovarian cancer multicellular spheroid (MCS) and explore the reversal effect of p27-antisense oligodeoxynucleotide (p27-ASON) on taxol resistance in ovarian cancer cell lines. METHODS: Three-dimensional culture was used to form MCS of human ovarian cancer cell lines A2780 and CAOV3. The MCSs were divided into 3 groups: MCSs transduced with p27-ASON or p27-sense oligodeoxynucleotide (p27-SON) by LipofectAMINE respectively and MCS without transduction. Monolayer A2780 and CAOV3 cells were cultured as controls. The cells were exposed to taxol of different concentrations (0.2, 2.0, 10.0, and 20.0 micro mol/L) for 24 hours. The expression of p27 in those cells was detected with Western blot and flow cytometry (FACS), and the subcellular distribution of p27 was detected by laser confocal microscopy before and after the experiment. The cell cycle profile and apoptosis were analyzed by FACS. The resistance to taxol was detected with trypan blue exclusion testing. RESULTS: Compared with that in monolayer cells, expression of p27 in MCS cells was significantly higher (P(A2780) = 0.011, P(CAOV3) = 0.024). The percentage of cells in G0-G1 phase was significantly higher in the MCS cells than in the monolayer cells, and the percentages of cells in S and G2-M phases were significantly lower in MCS cells than in monolayer cells. The apoptotic rate of the monolayer cells was significantly higher than those of MCS cells treated with taxol of the concentration of 20.0 micro mol/L (P(A2780) = 0.003, P(CAOV3) = 0.015). The apoptotic rate of p27-ASON/MCS was significantly higher than that of MCS (P(A2780) = 0.022, P(CAOV3) = 0.036). There was no significant difference of apoptotic rate between p27-SON/MCS and MCS (P(A2780) = 0.412, P(CAOV3) = 0.071). The monolayer A2780 and CAOV3 cells formed compact spheroids after three-dimensional culture. Cells transduced with p27-SON formed compact MCS too. However, cells tranduced with p27-ASON formed loose collections of cells easy to shatter. The expression of p27 in p27-ASON/MCSs was downregulated. CONCLUSION: The drug resistance of ovarian cancer MCS is related to upregulation of p27. P27-ASON reverses the resistance of ovarian cancer to taxol, thus increasing the chemotherapeutic sensitivity of ovarian cancer cells.

Antineoplastic Agents, Phytogenic↗
PubMed2002

Overexpression of a stabilized mutant form of the cyclin-dependent kinase inhibitor p27(Kip1) inhibits cell growth.

OBJECTIVE: The purpose of this study was to test the hypothesis that the expression of the mutant p27(Kip1) protein enhances cell growth inhibition and is more stable than that of the wild-type p27(Kip1). METHODS: Site-directed mutagenesis was used to mutate threonine 187 to an alanine residue, generating the mutant p27(Kip1). To study the effects of the p27(Kip1) mutant on cell growth, luciferase assays were performed. Cells were transiently transfected with the Renilla luciferase reporter construct and empty vector, wild-type p27(Kip1), or mutant p27(Kip1) using Fugene 6. The transfected cells were lysed and assayed for luciferase activity 24 h later with a dual-luciferase reporter assay system. To further assess the effects of the p27(Kip1) mutant on cell growth, colony count assays were performed. The experiments were repeated in duplicate and a standard two-tailed Student t test was use to analyze the data. RESULTS: Wild-type p27(Kip1) protein has a half-life of approximately 2 h while the p27(Kip1) mutant has a half-life of greater than 12 h. Furthermore, the p27(Kip1) mutant retained the ability to inhibit CDK2-associated H1 kinase activity. Cells expressing the p27(Kip1) mutant had an 88% reduction in luciferase activity compared to cells expressing the wild-type p27(Kip1) (P = 0.001). Colony assays revealed that cells expressing the p27(Kip1) mutant had fewer colonies compared to cells expressing the wild-type p27(Kip1) (P = 0.04). CONCLUSIONS: These data are consistent with the hypothesis that the mutated form of p27(Kip1) is more effective in cell growth inhibition than the wild-type p27(Kip1) protein.

Amino Acid Sequence↗
PubMed2005

Phosphorylation of extracellular signal-regulated kinase and p27(KIP1) after retinal detachment.

PURPOSE: The roles of the extracellular signal-regulated kinase (ERK) pathway in the expression of cyclin D1 and p27(KIP1), the phosphorylation of p27(KIP1), and proliferation activity were examined after retinal detachment. METHODS: Normal eyes and eyes at 15 min, 2 and 4 days after retinal detachment in C57Bl6 mice were examined by immunohistochemistry using anti-phosphorylated (p) ERK1/2, anti-cyclin D1, anti-p27(KIP1), anti-p27(KIP1) phosphorylated at serine 10 (S10-phospho-p27), and anti-proliferating cell nuclear antigen (PCNA) antibodies with or without treatment with a specific ERK inhibitor, PD98059. Mouse Müller cells were isolated and examined for alteration of p27(KIP1) and cyclin D1 after exposure of basic fibroblast growth factor (bFGF) with and without treatment of PD98059 using Western blotting. RESULTS: In the normal retina, nuclear immunoreactivity for p27(KIP1), but not S10-phospho-p27 or pERK1/2, was observed in the middle sublayer of the inner nuclear layer (INL), where Müller glial cells are situated. At 15 min after the retinal detachment, p27(KIP1), S10-phospho-p27 and pERK1/2-positive nuclei were noted in the INL, whereas immunoreactivity for pERK1/2 or S10-phospho-p27 was not observed after treatment with PD98095. Cyclin D1 was induced in the INL 2 days after the retinal detachment, and the induction was inhibited by PD98059. At 4 days after the detachment, p27(KIP1) immunoreactivity was not observed, and cyclin D1 and PCNA were expressed. The disappearance of p27(KIP1) was suppressed, whereas expression of cyclin D1 and PCNA was not observed in mice treated with PD98059. Exposure of bFGF relatively decreased the expression level of p27(KIP1) and increased the level of cyclin D1 in mouse Müller cells, compared with control level. Induction of cyclin D1 and decrease in p27(KIP1) were inhibited with treatment of PD98059. CONCLUSION: Phosphorylation of ERK and expression of p27(KIP1) and cyclin D1 are involved in the proliferation of Müller cells after retinal detachment.

Animals↗
PubMed1997

Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27.

The p27(Kip1) protein associates with G1-specific cyclin-CDK complexes and inhibits their catalytic activity. p27(Kip1) is regulated at various levels, including translation, degradation by the ubiquitin/proteasome pathway and non-covalent sequestration. Here, we describe point mutants of p27 deficient in their interaction with either cyclins (p27(c-)), CDKs (p27(k-)) or both (p27(ck-)), and demonstrate that each contact is critical for kinase inhibition and induction of G1 arrest. Through its intact cyclin contact, p27(k-) associated with active cyclin E-CDK2 and, unlike wild type p27, p27(c-) or p27(ck-), was efficiently phosphorylated by CDK2 on a conserved C-terminal CDK target site (TPKK). Retrovirally expressed p27(k-) was rapidly degraded through the proteasome in Rat1 cells, but was stabilized by secondary mutation of the TPKK site to VPKK. In this experimental setting, exogenous wild-type p27 formed inactive ternary complexes with cellular cyclin E-CDK2, was not degraded through the proteasome, and was not further stabilized by the VPKK mutation. p27(ck-), which was not recruited to cyclin E-CDK2, also remained stable in vivo. Thus, selective degradation of p27(k-) depended upon association with active cyclin E-CDK2 and subsequent phosphorylation. Altogether, these data show that p27 must be phosphorylated by CDK2 on the TPKK site in order to be degraded by the proteasome. We propose that cellular p27 must also exist transiently in a cyclin-bound non-inhibitory conformation in vivo.

Amino Acid Sequence↗
PubMed1999

Low p27 expression correlates with poor prognosis for patients with oral tongue squamous cell carcinoma.

BACKGROUND: p27, a cyclin-dependent kinase inhibitor, regulates progression from G1 to S phase. There have been a few clinical reports of low p27 expression associated with poor survival among patients with cancer; however, there have been no reports of such an association in cases of head and neck cancer. The authors investigated whether p27 expression in patients with oral tongue squamous cell carcinoma was associated with their prognosis. METHODS: Ninety-four patients with oral tongue squamous cell carcinoma were analyzed. The authors performed p27 immunohistochemistry on all patients and Western blot analysis on 19 available patients. Cox proportional hazards regression analysis that included gender, history of smoking and alcohol usage, presence of multiple primary cancers, stage, histologic grade, and p27 status was used to identify the multivariate predictive value of prognostic factors. RESULTS: Twenty-six patients had high p27 expression (> or =50% tumor cell nuclei positive), and 68 patients had low p27 expression (<50%) by immunohistochemistry. In those with low p27 expression, N(+) and advanced T (T3 or T4) were significantly higher than in those with high p27 expression (P = 0.02 and 0.04). The 5-year survival rate in the low p27 group was 44%, whereas that in the high p27 group was 68%, indicating a significant difference (P = 0.04). p27 expression was inferred from Western blot analysis, and an arbitrary quantity (<1, 1-5, or > or =5) from the ratio of tumor to normal tissue density was used to characterize, resulting in 8 (42%), 3 (16%), and 8 (42%) patients in the low (<1-fold), intermediate (1-5-fold), and high (> or =5-fold) groups, respectively. Results of immunohistochemical analysis for p27 were significantly correlated with those of Western blot analysis (P = 0.02). Multivariate analysis revealed that low intensity of p27 expression and advanced stage (Stage III or IV) were predictors of reduced survival (P = 0.02 and 0.001). CONCLUSIONS: Low p27 expression was associated with increasing lymph node metastasis and stage of tumor and resulted in a poor prognosis for patients with oral tongue squamous cell carcinoma. p27 is apparently a significant predictor of survival.

Actins↗
PubMed2003

p27 Kip1 expression is reduced in pancreatic carcinoma but has limited prognostic value.

p27(Kip1) is a cyclin-dependent kinase inhibitor whose loss in malignant tumors is associated with disease progression and an unfavorable clinical outcome. There is limited information about its expression in pancreatic carcinomas. In a previous Japanese study, p27(Kip1) loss was a powerful negative prognostic factor. In the present study, we assessed the expression of p27(Kip1) in resected pancreatic ductal adenocarcinomas from 46 European patients and in associated lymph node metastases from 13 patients, using a standard avidin-biotin peroxidase complex immunohistochemical method. We also analyzed the relationships among p27(Kip1) expression, pathologic features, and clinical outcome. The extent of p27(Kip1) expression (ie, the percentage of cells expressing p27(Kip1)) was lower in carcinomas than in nonneoplastic ductal epithelia. Carcinomas with <5% p27(Kip1) expression were more likely to be poorly or moderately differentiated than well differentiated (P =.022). p27(Kip1) expression did not correlate with patient gender, tumor maximum dimension, T classification, lymph node metastasis, or International Union Against Cancer stage. No significant difference was seen between the extent of p27(Kip1) expression in lymph node metastases and their corresponding primary tumors. Univariate survival analysis showed that an increased risk of death was associated with 2 established prognostic factors: tumor size >5 cm (P =.011) and incomplete surgical excision (P =.016). Trends toward worse survival for patients whose primary tumors had <4% p27(Kip1) expression (P =.060) and for patients whose lymph node metastases had <5% p27(Kip1) expression (P =.054) were seen, but multivariate analysis suggested that p27(Kip1) expression was not independently prognostic. The findings raise the possibility that abnormalities of p27(Kip1) play a role in the pathogenesis of pancreatic ductal adenocarcinoma. However, the extent of p27(Kip1) expression in lymph node metastases and primary tumors is similar. Also, reduced p27(Kip1) expression has limited prognostic value, at least in European patients.

Adenocarcinoma↗