• Journal of Gastric Cancer
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• 제6권1호
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• pp.36-42
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• 2006

목적: 암의 발생과 진행에 있어서 비정상적인 세포주기로 인하여 조절이 불가능한 세포성장과 분열이 중요한 기전으로 관여한다. 세포주기는 cyclin, CDK와 cyclin의 복합체는 CDKI에 의해 억제된다. 세포주기를 억제하는 인자는 종양 세포에서도 종양억제인자로 작용한다. 세포 주기 조절인자 CDKI는 INK family, CIP/KIP family로 구분된다. 본 연구는 CIP/KIP family인 $p21^{Waf1/Cip1}\;27^{kip1}$ 단백질의 발현유무에 따른 위암의 임상조직학적인 특성 및 예후와 연관성에 대해 조사하였다. 대상 및 방법: 1993년부터 1997년까지 위암으로 진단받고 수술적 치료를 받은 환자들 중에 추적 조사가 가능하고 파라핀 포매 조직상태가 좋은 192명의 환자를 대상으로 하였다. $p21^{Waf1/Cip1}$과$p27^{kip1}$에 대해 면역조직화학염색을 시행하였고, 종양세포의 핵에 염색되는 세포를 양성 판정하였다. 통계학적 분석은 임상조직학적인 특성과 생존율의 차이에 대하여 시행하였다. 결과: $p21^{Waf1/Cip1}$은 15.6% (30/192), $p27^{kip1}$은 28.1% (54/192)의 발현율을 보였다. $p21^{Waf1/Cip1}$은 양성에서는 T1-2 (80.0%), 음성에서는 T3-4 (50.6%)가 차지하는 비율이 높았으며(P<0.05) 다른 인자에서는 통계적인 유의성이 없었다. $p27^{kip1}$에서는 T-stage에서 $p21^{Waf1/Cip1}$과 비슷한 결과(77.8%, 55.1%)를 보였으며, Lauren 분류에서는 장형(62.7%)보다 미만형(91.3%)에서 음성을 보이는 비율이 높았다.(P<0.05)$p27^{kip1}$도 다른 인자에서는 통계적인 유의성이 없었다. 의 상관관계는 $p21^{Waf1/Cip1}(+)$과 $p27^{kip1}$의 상관관계는 $p21^{Waf1/Cip1}(+)/p27^{kip1}(+)$ 보이는 경우(53.3%)와, $p21^{Waf1/Cip1}(-)/p27^{kip1}(-)$ 보이는 경우(76.5%)가 많았다(P<0.05). $p21^{Waf1/Cip1}$과 $p27^{kip1}$ 복합 검사에서는 $p21^{Waf1/Cip1}(+)/p27^{kip1}(+)$인 경우에 T1-2 (87.5%)가 많았고 $p21^{Waf1/Cip1}(-)/p27^{kip1}(-)$인 경우에는 T3-4(58.1%)가 많았다(P<0.05). 또한 Lauren 분류에서는 $p21^{Waf1/Cip1}(+)/p27^{kip1}$인 경우가 장형 (100%)에서만 나타났으며(P<0.05), $p21^{Waf1/Cip1}(-)/p27^{kip1}(-)$인 경우는 미만형인 경우(87.0%)가 장형(54.9%)의 경우보다 많은 비율을 차지하였다(P<0.05). 5년 장기 생존율에 있어서는 각각의 $p21^{Waf1/Cip1}$과$p27^{kip1}$의 발현 유무에 따른 통계적인 유의성은 없었고 복합 검사에서도 $p21^{Waf1/Cip1}(+)/p27^{kip1}(+)$의 경우에 생존율이 높았지만 통계적인 유의성은 없었다. 결론: 저자들의 경우에는 $p21^{Waf1/Cip1}$과$p27^{kip1}$은 서로 비슷한 발현 형태를 나타내고 $p21^{Waf1/Cip1}$과$p27^{kip1}$의 발현은 침윤 정도에 영향을 주며, $p27^{kip1}$의 경우에는 Lauren분류와 관련성이 있었다. 또한, $p21^{Waf1/Cip1}$과$p27^{kip1}$ 복합 검사는 침윤 정도와 Lauren 분류와 연관성이 있다고 할 수 있다. 하지만, $p21^{Waf1/Cip1}$과$p27^{kip1}$의 발현에 따른 생존율의 차이가 유의성을 보이지 않아, 예후 예측인자로의 적용은 한계가 있다고 생각한다.

• 대한의생명과학회지
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• 제14권4호
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• pp.243-248
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• 2008

The Forkhead box M1 (FoxM1) has been shown to regulate transcription of cell cycle genes essential for $G_1$-S and $G_2$-M progression, including $p27^{kip1}$. The $p27^{kip1}$ gene is a member of the universal cyclin-dependent kinase inhibitor family. Immunohistochemical studies for FoxM1 and $p27^{kip1}$ were performed in 154 lung cancers (69 squamous cell carcinomas (SCC) and 85 adenocarcinomas (ADC)). Immunoreactivity for FoxM1 and $p27^{kip1}$ were found in 79 (51.3%) and 49 (31.8%) out of 154 cases, respectively. Forty-six (58.2%) of the 79 cases with a positive FoxM1 immunoreactivity showed a negative $p27^{kip1}$ expression in 154 lung cancers. According to histologic type, 22 (53.7%) of the 41 SCC cases with a positive FoxM1 immunoreactivity showed a negative $p27^{kip1}$ expression and 24 (63.2%) of the 38 ADC cases with a positive FoxM1 immunoreactivity showed a negative $p27^{kip1}$ expression. The expression of $p27^{kip1}$ was significantly higher in the SCC than in the ADC (P=0.050). There were no significant associations between the FoxM1 and $p27^{kip1}$ expressions and other clinicopathologic factors. These findings suggest that FoxM1 overexpression may diminish the expression of $p27^{kip1}$ protein in lung cancers. Further studies are needed to define the relation between FoxM1 and $p27^{kip1}$ for examining the mechanisms of tissue-specific FoxM1 expression.

• Journal of Korean Neurosurgical Society
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• 제30권4호
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• pp.443-450
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• 2001

Objective : The cyclin-dependent kinase inhibitor $p27^{kip1}$ protein is a negative regulator of the cell cycle, and its degradation is required for entry into the S phase. Loss of $p27^{kip1}$ expression has been reported to be associated with aggressive behavior in a variety of tumors of epithelial and lymphoid origin. However, its association with various astrocytic tumors has not been clearly demonstrated. We studied to investigate the relationship of $p27^{kip1}$ expression with the biological behavior of astrocytic tumors in addition to study on the role of $p27^{kip1}$ in the tumorigenesis of these tumors. Patients and Methods : From 1990 to 1998, a total of 29 astrocytic tumor of all grades obtained by operative resection were included for evaluation. We studied the expression of $p27^{kip1}$ protein immunohistochemical assay in astrocytic tumors and compared the findings with the clinicopathologic parameters. Immunohistochemical staining was performed on formalin-fixed paraffin-embedded sections by the avidin-biotin-peroxidase complex method. According to WHO classification, all cases were divided into astrocytomas(4 cases), anaplastic astrocytomas(9 cases), and glioblastomas(16 cases) by 3 pathologists. Clinical information was obtained from medical records, and others such as location and size of tumors from imaging studies. Results : Mean $p27^{kip1}$ protein labeling indexes(LI, mean${\pm}$standard deviation) of astrocytomas, anaplastic astrocytomas, and glioblastomas were $80.6{\pm}9.1$, $63.6{\pm}21.0$, and $28.9{\pm}18.7$, respectively, and were inversely correlated with grade of glial tumors(p<0.0001). Mean $p27^{kip1}$ protein LI in the recurrent group was lower than that in the nonrecurrent group, but there was no significant difference statistically(p=0.464). Additionally, $p27^{kip1}$ protein expression did not show any significant relationship to other prognostic factors such as age(p=0.1643), tumor size(p=0.8), or location(p=0.8). Conclusion : These results suggested that reduced expression of $p27^{kip1}$ protein may play a important role in the malignant transformation process of astrocytic tumor cells.

• Journal of Microbiology and Biotechnology
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• 제22권12호
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• pp.1790-1794
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• 2012

Recently, it has been suggested that $p27^{Kip1}$, the cell cycle regulatory protein, plays a pivotal role in the progression of normal differentiation in murine embryonic stem (mES) cells. In the current study, we investigated the role of $p27^{Kip1}$ in the regulation of differentiation and apoptotic induction using Western blotting, quantitative real-time RT-PCR, and small interfering RNA (siRNA) assays and confocal laser scanning microscopic analysis of H9 human ES (hES) cells and H9-derived embryoid bodies (EBs) grown for 10 ($EB_{10}$) and 20 days ($EB_{20}$). Our results demonstrate that the proteins $p27^{Kip1}$ and cyclin D3 are strongly associated with cellular differentiation, and, for the first time, show that up-regulation of $p27^{Kip1}$ protects hES cells from inducing differentiation-associated and caspase 3-dependent apoptosis.

• The Korean Journal of Physiology and Pharmacology
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• 제23권3호
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• pp.171-179
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• 2019

Pituitary tumors are usually benign but can occasionally exhibit hormonal and proliferative behaviors. Dysregulation of the G1/S restriction point largely contributes to the over-proliferation of pituitary tumor cells. F-box protein S-phase kinase-interacting protein-2 (SKP2) reportedly targets and inhibits the expression of $p27^{Kip1}$, a well-known negative regulator of G1 cell cycle progression. In this study, SKP2 expression was found to be upregulated while $p27^{Kip1}$ expression was determined to be downregulated in rat and human pituitary tumor cells. Furthermore, SKP2 knockdown induced upregulation of $p27^{Kip1}$ and cell growth inhibition in rat and human pituitary tumor cells, while SKP2overexpression elicited opposite effects on $p27^{Kip1}$ expression and cell growth. The expression of microRNA-186 (miR-186) was reported to be reduced in pituitary tumors. Online tools predicted SKP2 to be a direct downstream target of miR-186, which was further confirmed by luciferase reporter gene assays. Moreover, miR-186 could modulate the cell proliferation and $p27^{Kip1}$-mediated cell cycle alternation of rat and human pituitary tumor cells through SKP2. As further confirmation of these findings, miR-186 and $p27^{Kip1}$ expression were downregulated, while SKP2 expression was upregulated in human pituitary tumor tissue samples; thus, SKP2 expression negatively correlated with miR-186 and $p27^{Kip1}$ expression. In contrast, miR-186 expression positively associated with $p27^{Kip1}$ expression. Taken together, we discovered a novel mechanism by which miR-186/SKP2 axis modulates pituitary tumor cell proliferation through $p27^{Kip1}$-mediated cell cycle alternation.

• 대한의생명과학회지
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• 제16권2호
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• pp.71-74
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• 2010

Cell proliferation is governed by precise and orderly process the regulation of which involves many different proteins. The key enzyme for cell growth and arrest is cyclin dependent kinases (cdks). In human cells, several cdks orchestrate four distinct cell cycle phases (M, $G_1$, S and $G_2$ ) and they sequentially operate in an order of cdc1, cdk4, cdk6 and cdk2. The regulatory components of cdks consist of cyclins and two family of cdk inhibitors, INK4 (inhibitors of cdk4) and KIP (kinase inhibitor protein). $G_1$ regulatory molecules for cdk mainly respond to environmental cues of mitogenic and anti-mitogenic stimuli and therefore influence activities of $G_1$ cdks, namely, cdk4/6 and cdk2. $G_1$ inhibitors include $p21^{CIP}$ and $p27^{KIP1}$. Between them, $p27^{KIP1}$ has attracted attentions of many researchers because of its characteristic regulatory features and diverse functions. Besides, the role of $p27^{KIP1}$ in cancer development warrants further studies in the future. Therefore, this review will focus on the recent findings and especially on the complexity of regulatory mechanisms of $p27^{KIP1}$.

• Biomolecules & Therapeutics
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• 제15권4호
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• pp.218-223
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• 2007

T cell proliferation is a pivotal to an effective immune response. Cyclin-dependent kinase (cdk) inhibitor, $p27^{kip1}$ is degraded to initiate T cell expansion. In this study, we show that although the expression of $p27^{kip1}$ protein was down-regulated, that of $p21^{cip1}$, another cdk inhibitor, was up-regulated in $CD8^+$ T cells following in vitro stimulation. Ex vivo gB antigen-stimulation following HSV immunization increased $p21^{cip1}$ positive cells that co-expressed IFN-$\gamma$. Moreover, $p21^{cip1}$ was co-expressed with IFN-${\gamma}$ in E7 antigen-stimulated $CD8^+$ T cells, whereas $p27^{kip1}$ was not. Our findings imply a role of $p21^{cip1}$ proteins in antigen-induced effector $CD8^+$ T cells differentiation in vivo.

• 대한두경부종양학회지
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• 제17권2호
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• pp.139-147
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• 2001

Objectives: The most important differential point of follicular carcinoma from adenoma is capsular invasion or angioinvasion of follicular cells. Serial sections for examination of levels of tumor margins are necessary to watch the invasion. However, the interpretation of capsular invasion or angioinvasion is sometimes not feasible on the routine staining of tumor tissue. The aim of this study is to evaluate the clinical significance of expressions of $p27^{KIP1}$, MIB-1, bcl-2 and p53 in differential diagnosis of follicular adenoma and carcinoma. Materials and Methods: 16 cases of follicular carcinoma and 26 cases of follicular adenoma were entered on study of immunohistochemical stains for $p27^{KIP1}$, MIB-1, bcl-2 and p53. In carcinoma cases, correlation between the above markers, patient's age, tumor size, infiltration pattern and metastasis was studied. Results: $p27^{KIP1}$ labelling index (LI) of follicular carcinoma and adenoma was $4.89{\pm}6.92$ and $14.52{\pm}9.17$, respectively, but there was no significant difference between adenoma and carcinoma (p=0.2560). MIB-1 LI of carcinoma and adenoma was $4.11{\pm}3.89$ and $0.80{\pm}0.75$, respectively, and MIB-1 LI was significantly higher in carcinoma (p=0.0000). bcl-2 expression was seen in 2(12.5%) of 16 carcinoma cases and 130(50.0%) of 26 adenoma cases, and bcl-2 expression rate was higher in adenoma than in carcinoma(p=0.014). In one adenoma and one carcinoma case, p53 expression was noted. In follicular adenoma with atypia compared to adenoma without atypia, lower $p27^{KIP1}$ LI, higher MIB-1 LI and lower bcl-2 expression rate were seen. In follicular carcinoma, MIB-1 LI was significantly higher in invasive carcinoma(p=0.045) and was relatively increased in tumors larger than 3.0cm, showing angioinvasion and distant metastasis. But $p27^{KIP1}$ LI was higher in cases over 40 years old(p=0.008) and with conspicuous capsular invasion. There were no positive correlations between expressions of MIB-1, bcl-2 and p53. Conclusion: MIB-1 labelling index and bcl-2 expression could be helpful for differential diagnosis of follicular adenoma and carcinoma, but p53 showed very low expression rate and no significance in differential diagnosis. $p27^{KIP1}$ labelling index reveals decreasing tendency in carcinoma compared with adenoma, MIB-1 LI was considered as a poor prognostic marker in follicular carcinoma, but $p27^{KIP1}$ LI was higher in carcinoma cases over 40 years old with showing conspicuous capsular invasion. Further study for the significance of $p27^{KIP1}$ labelling index in follicular neoplasms is necessary to evaluate diagnostic value of follicular carcinoma.

• BMB Reports
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• 제43권3호
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• pp.199-204
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• 2010

The protein p104 was first isolated as a binding partner of the Src homology domain of phospholipase C$\gamma$1, and has been shown to associate with p85$\alpha$, Grb2. The ectopic expression of p104 reduced cellular growth rate, which was also achieved with the overexpression of only the proline-rich region of p104. The proline-rich region of p104 has been found to inhibit the colony formation of platelet-derived growth factor BB-stimulated NIH3T3 cells and MCF7 cancer cells on soft agar. Mutagenesis analysis showed that the second and third proline-rich regions are essential for growth control, as well as for interaction with p85$\alpha$. Overexpression of p104 increased the level of the cyclin-dependent kinase inhibitor, $p27^{Kip1}$, and inhibited the activity of phosphoinositide 3-kinase (PI3K). In summary, p104 interacts with p85$\alpha$ and is involved in the regulation of $p27^{Kip1}$ expression for the reduction of cellular proliferation.

• Animal cells and systems
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• 제9권4호
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• pp.191-198
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• 2005

The effects of 6-aminonicotinamide (6-AN) on viability of IMR32 neuroblastoma cells in the presence of ATP or $NAD^+$ have been investigated. 6-AN caused marked reduction in cell viability and similar observations were also made with cells treated with 6-AN+ATP. However, cells treated with $6-AN+NAD^+$ showed cell viability similar to untreated cells. Morphologically, 6-AN and 6-AN+ATP treated cells showed loss of neurites, polyhedric shapes, shrinkage of cell bodies and formation of lysed cells, while $6-AN+NAD^+$ cells did not show any such changes. The flow cytometry analysis demonstrated that 6-AN increased cell population in $G_0/G_1$ phase and decreased cell population in Sand $G_2/M$ phase following a 72 h exposure. Western blot analysis showed that 6-AN stimulated a substantial increase in the level of the cdk inhibitor $p27^{kip1}$, but lowered the levels of cdk2, cyclin E and p-Rb. However, cdc25A and p53R2 were not significantly affected. Immunofluorscence staining of $p27^{kip1}$, cdk2, cyclin E and p-Rb revealed close correlation between the signal observed in the Western blot analysis. 6AN+ATP treated cells showed similar results obtained with 6-AN treated cells in expression of cdk2, cyclin E, p-Rb proteins and $p27^{kip1}$, $6-AN+NAD^+$ cells showed greater expression of cdk2, cyclin E and p-Rb than those in 6-AN and 6-AN+ATP treated cells. The results suggest that 6-AN induced the $G_0/G_1$ phase arrest in IMR32 neuroblastoma cell lines through the increase of $p27^{kip1}$ and the decrease of cdk2, cyclin E and p-Rb.