Functional Inactivation of pRb Associated with Cyclin D1- and Cyclin-dependent Kinase 4 Overexpression Plays A Key Role in Human Pituitary Tumorigenesis

명나혜 대한병리학회 2009 Journal of Pathology and Translational Medicine Vol.43 No.1

Background : Human pituitary adenoma (PA) is a common intracranial tumor, but the mechanism underlying tumorigenesis has not been established. Functional inactivation of retinoblastoma protein (pRb) following cyclin D1- and cyclin-dependent kinase (CDK) 4-dependent hyperphosphorylation is one of the most important mechanisms in tumor cell proliferation. We evaluated immunohistochemical expressions of cyclin D1, CDK4 and phosphorylated pRb (p-pRb) in 50 PAs to investigate a role for functional inactivation of pRb associated with cyclin D1/CDK4 overexpression in pituitary tumorigenesis and to correlate it with clinicopathologic variables. Methods : Fifty human PAs were immunohistochemically stained for cyclin D1, CDK4 and p-pRb (Thr 356). Correlations between their expression and the clinicopathologic characteristics were statistically analyzed. Results : Cyclin D1 and CDK4 were overexpressed in 56% and 64%, respectively; pRb was hyperphosphorylated in 64%. Forty one cases (82%) showed one or more of these altered expressions. Overexpressions of cyclin D1 and CDK4 were correlated with functional pRb inactivation. Cyclin D1 overexpression was associated with apoplexy and growth hormone production. Conclusions : Functional inactivation of pRb associated with the cyclin D1/CDK4 overexpression might play a key role in human pituitary tumorigenesis. CDK4 worked in concert with cyclin D1 to hyperphosphorylate pRb. Pituitary apoplexy appeared to be associated with cyclin D1 overexpression. Background : Human pituitary adenoma (PA) is a common intracranial tumor, but the mechanism underlying tumorigenesis has not been established. Functional inactivation of retinoblastoma protein (pRb) following cyclin D1- and cyclin-dependent kinase (CDK) 4-dependent hyperphosphorylation is one of the most important mechanisms in tumor cell proliferation. We evaluated immunohistochemical expressions of cyclin D1, CDK4 and phosphorylated pRb (p-pRb) in 50 PAs to investigate a role for functional inactivation of pRb associated with cyclin D1/CDK4 overexpression in pituitary tumorigenesis and to correlate it with clinicopathologic variables. Methods : Fifty human PAs were immunohistochemically stained for cyclin D1, CDK4 and p-pRb (Thr 356). Correlations between their expression and the clinicopathologic characteristics were statistically analyzed. Results : Cyclin D1 and CDK4 were overexpressed in 56% and 64%, respectively; pRb was hyperphosphorylated in 64%. Forty one cases (82%) showed one or more of these altered expressions. Overexpressions of cyclin D1 and CDK4 were correlated with functional pRb inactivation. Cyclin D1 overexpression was associated with apoplexy and growth hormone production. Conclusions : Functional inactivation of pRb associated with the cyclin D1/CDK4 overexpression might play a key role in human pituitary tumorigenesis. CDK4 worked in concert with cyclin D1 to hyperphosphorylate pRb. Pituitary apoplexy appeared to be associated with cyclin D1 overexpression.

후두와 하인두 편평세포암종에서 Ki-67표지지수와 Cyclin D1 발현의 예후적 의미

소상훈,송병철,정인교,노영수,임현준,김덕환 대한이비인후과학회 1999 대한이비인후과학회지 두경부외과학 Vol.42 No.5

비강 및 부비동 종양에서의 p53, p21, Cyclin D1, Ki-67 발현

정하민,윤기중,이재훈 대한비과학회 2008 Journal of rhinology Vol.15 No.2

Background and Objectives:The goal of this study is to investigate alterations of cell-cycle-related molecules, including p53, p21, cyclin D1 and Ki-67, in tumors arising in the sinonasal region. Materials and Methods:The study materials were 16 specimens of normal nasal mucosa, 16 inverted papillomas (IPs) and 12 sinonasal squamous cell carcinomas. The p53, p21, cyclin D1 and Ki-67 expression was assessed by immunohistochemical staining. Result:IP and squamous cell carcinoma showed significant increase in the expression of p53, cyclin D1 and Ki-67 than normal mucosa. The expression of p53, cyclin D1 and Ki-67 of the carcinoma was stronger than the IP. But, the p21 expression was not associated with the IP and carcinoma. Conclusion:Increased levels of p53, cyclin D1 and Ki-67 expression correlate with increased cell proliferation in the tumors of sinonasal regions. These findings indicate that p53, cyclin D1 and Ki-67 expression may be useful markers for the dysregulations of cell kinetics in the tumors of sinonasal region. Background and Objectives:The goal of this study is to investigate alterations of cell-cycle-related molecules, including p53, p21, cyclin D1 and Ki-67, in tumors arising in the sinonasal region. Materials and Methods:The study materials were 16 specimens of normal nasal mucosa, 16 inverted papillomas (IPs) and 12 sinonasal squamous cell carcinomas. The p53, p21, cyclin D1 and Ki-67 expression was assessed by immunohistochemical staining. Result:IP and squamous cell carcinoma showed significant increase in the expression of p53, cyclin D1 and Ki-67 than normal mucosa. The expression of p53, cyclin D1 and Ki-67 of the carcinoma was stronger than the IP. But, the p21 expression was not associated with the IP and carcinoma. Conclusion:Increased levels of p53, cyclin D1 and Ki-67 expression correlate with increased cell proliferation in the tumors of sinonasal regions. These findings indicate that p53, cyclin D1 and Ki-67 expression may be useful markers for the dysregulations of cell kinetics in the tumors of sinonasal region.

The involvement of cyclin D1 degradation through GSK3β-mediated threonine-286 phosphorylation-dependent nuclear export in anti-cancer activity of mulberry root bark extracts

Eo, H.J.,Park, G.H.,Jeong, J.B. G. Fischer 2016 Phytomedicine Vol.23 No.2

<P>Background: Mulberry root bark was shown to induce cyclin D1 proteasomal degradation in the human colorectal cancer cells. Still, the molecular mechanisms whereby mulberry root bark induces cyclin D1 proteasomal degradation remain largely unknown. Purpose: In this study, the inhibitory effect of mulberry root bark (MRB) on the proliferation of human colorectal cancer cells and the mechanism of action were examined to evaluate its anti-cancer activity. Methods: Anti-proliferative effect was determined by MTT assay. RT-PCR and Western blotting were used to assess the mRNA and protein expression of related proteins. Results: MRB inhibited markedly the proliferation of human colorectal cancer cells (HCT116, SW480 and LoVo). In addition, the proliferation of human breast cancer cells (MDA-MB-231 and MCF-7) was suppressed by MRB treatment. However, MRB did not affect the growth of HepG-2 cells as a human hepatocellular carcinoma cell line. MRB effectively decreased cyclin D1 protein level in human colorectal cancer cells and breast cancer cells, but not in hepatocellular carcinoma cells. Contrast to protein levels, cyclin D1 mRNA level did not be changed by MRB treatment. Inhibition of proteasomal degradation by MG132 attenuated MRB-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in the cells treated with MRB. In addition, MRB increased phosphorylation of cyclin D1 at threonine-286 and a point mutation of threonine-286 to alanine attenuated MRB-mediated cyclin D1 degradation. Inhibition of GSK3 beta by LiCl suppressed cyclin D1 phosphorylation and downregulation by MRB. MRB decreased the nuclear level of cyclin D1 and the inhibition of nuclear export by LMB attenuated MRB-mediated cyclin D1 degradation. Conclusion: MRB has anti-cancer activity by inducing cyclin D1 proteasomal degradation through cyclin D1 nuclear export via GSK3 beta-dependent threonine-286 phosphorylation. These findings suggest that possibly its extract could be used for treating colorectal cancer. (C) 2015 Elsevier GmbH. All rights reserved.</P>

Longer Survival in Patients with Breast Cancer with Cyclin D1 Over- Expression after Tumor Recurrence: Longer, but Occupied with Disease

정재식,노하니,최은희,박광화,한애리 한국유방암학회 2014 Journal of breast cancer Vol.17 No.1

Purpose: The effect of cyclin D1 overexpression on breast canceroutcomes and prognosis is controversial, even though amplificationof the cyclin D1 gene, CCND1, has been shown to be associatedwith early relapse and poor prognosis. In this study, we examinedthe relationship between cyclin D1 overexpression anddisease-specific survival (DSS). We also analyzed survival in patientswho experienced recurrence. Methods: We retrospectivelyanalyzed data from patients diagnosed with ductal carcinomabetween April 2005 and December 2010. We examined clinicopathologicfactors associated with cyclin D1 overexpression andanalyzed the influence of cyclin D1 on recurrence-free survivaland DSS. Results: We identified 236 patients diagnosed with primarybreast cancer who completed all phases of their primarytreatment. Cyclin D1 overexpression was significantly associatedwith longer DSS (5-year DSS, 89.9% in patients without cyclin D1overexpression vs. 98.9% in patients with cyclin D1 overexpression;p=0.008). Multivariate analysis also found that patients withcyclin D1 overexpressing tumors had significantly longer diseasespecificsurvival than patients whose tumors did not overexpresscyclin D1, with a hazard ratio for disease-specific mortality of 7.97(1.17–54.22, p=0.034). However, in the group of patients whoexperienced recurrence, cyclin D1 overexpression was not significantlyassociated with recurrence-free survival. Cyclin D1 overexpressionwas significantly associated with increased survivalafter disease recurrence, indicating that cyclin D1 overexpressionmight be indicative of more indolent disease progression aftermetastasis. Conclusion: Cyclin D1 overexpression is associatedwith longer DSS, but not recurrence-free survival, in patients withbreast cancer. Longer postrecurrence survival could explain theapparent inconsistency between DSS and recurrence-free survival. Patients with cyclin D1-overexpressing tumors survive longer,but with metastatic disease after recurrence. This informationshould spark the urgent development of tailored therapies to curethese patients

Estrogen-Induced Cyclin D1 and D3 Gene Expressions During Mouse Uterine Cell Proliferation In Vivo : Differential Induction Mechanism of Cyclin D1 and D3

GEUM, DONGHO,SUN, WOONG,PAIK, SANG KI,LEE, CHUNG CHOO,KIM, KYUNGJIN 충남대학교 생물공학연구소 1998 생물공학연구지 Vol.6 No.-

D-type cyclins are involved in the regulation of the G_1/S transition of the cell cycle in various cell types cultured in vitro. Little is, however, known about the expression pattern and functional role of D-type cyclins in physiological processes in vivo. In this report, we studied whether the expression of murine D-type cyclins correlates with the states of mouse uterine cell proliferation in vivo. Time-course changes in cyclin D1 and D3 mRNA levels in the uterine tissues of immature mice primed with 17β-estradiol(E_2)were examined by Northern blot hybridization. c-fos and thymidine kinase (TK) mRNA levels were also examined as markers for the transition from G_0 to G_1 and the onset of S phase, respectively. Cyclin D1 and D3 mRNAs were induced 2.5-fold between c-fos and TK mRNA peaks. The E_2-induced cyclin D1 and D3 gene expressions were blocked by antiestrogens tamoxifen and ICI 182, 780. We also investigated the effects of cycloheximide (CHX), a protein synthesis inhibitor, on cyclin D1 and D3 gene expressions. When CHX was treated alone, cyclin D3, but not cyclin D1, mRNA was immediately superinduced. The E_2-induced cyclin D3 gene expression was shifted by approximately 6 h when CHX was pretreated 1 hr before E_2 administration. Interestingly, the ^3H-thymidine incorporation experiment showed that the mouse uterine cell cycle progression also shifted by 6 hr with pretreatment of CHX. The overall results suggest that both cyclin D1 and D3 mRNAs are constitutively expressed in uterine tissues and induced by E_2 at G_1 phase of the mouse uterine cell cycle. However, the superinducibility and temporal shift of cyclin D3 by CHX suggest that there is a different regulatory mechanism underlying cyclin D1 and D3 gene expressions in the mouse uterine cell cycle progression. Mol. Reprod. Dev. 46:450-458, 1997. ⓒ 1997 Wiley-Liss, Inc.

자궁내막암조직에서 세포주기 조절단백 G1 cyclins의 발현과 임상적 예후인자와의 상관관계

김영태,김성훈,김재욱,이진우,박기현 대한부인종양 콜포스코피학회 2003 Journal of Gynecologic Oncology Vol.14 No.1

목적 : 서구화과정과 더불어 우리나라에서 점차 많은 발생빈도를 보이는 자궁내막암조직 RNA level에서의 cyclin의 발현을 호르몬수용체와 연관하여 조사하였으며 그 결과와 임상적 예후인자와의 관련성을 알아보고자 본 연구를 시행하였다. 연구 방법 연세대학교 의과대학 산부인과학교실에 내원하여 자궁내막암으로 확진된 환자 33명과 양성 부인과 종양으로 전자궁절제술을 시행받은 대조군 환자 9명의 자궁내막조직을 대상으로 에스트로겐수용체 및 프로제스테론수용체를 효소면역분석법으로 조사하였으며 세포주기인자중에서 cyclin Dl과 cyclin I의 발현을 연구하였다. 결과 :자궁내막암조직과 대조군의 에스트로겐수용체 및 프로제스테론수용체의 양성률을 조사한 결과에서 에스트로겐수용체 및 프로제스테론수용체의 농도는 자궁내막암조직에서 보다 정상대조군에서 높게 나타났는데 대조군에서 에스트로겐수용체는 100%에서 양성률을 보였고 평균농도는 162.1±13.8 fmole/mg이었던 반면에 자궁내막암에서는 76%에서 양성률을 보였고 평균농도는 98.5±18.2 fmole/mg이었다. 또한 프로제스테론수용체는 정상대조군에서 마찬가지로 100% 양성률을 보였고 평균농도는 211.1±12.8 fmole/mg이었던 반면에 악성조직에서는 67%의 양성률과 평균농도 62.1±3.8 fmole/mg을 보여 대조군과 자궁내막암 조직간의 유의한 차이를 보이지 않았으나 자궁내막암조직에서는 대조군의 정상자궁내막에 비해 호르몬수용체의 농도가 낮게 났다. 내막암군에서의 cyclin Dl의 transcript의 과발현양상과 임상병리학적 제예후인자와의 관련성을 분석한 결과, 종양분화도, 자궁근층침법도, 병기, 림프절전이 유무, 세포형태, 프로제스테론수용체 양성율과는 통계적으로 유의한 차이를 보이지 않았고 에스트로겐수용체에 따라서는 cyclin Dl의 과발현이 통계학적으로 유의한 차이를 나타내었다. cyclinI의 transcript의 과발현양상과 임상병리학적 제예후인자와의 관련성을 분석한 결과에서도 종양분화도, 자궁근층침법도, 병기, 림프절전이 유무, 세포형태와는 통계적으로 유의한 차이를 보이지 않았으나 호르몬수용체 음성군에서는 cyclin I의 과발현이 통계학적으로 유의하게 높게 나타났다. 결론 cyclin Dl 및 I의 과발현이 자궁내막암의 여러 임상병리학적인 예후인자들과 밀접한 관련성을 나타내지는 않았지만 호르몬 수용체와는 연관성이 있음을 알 수 있었다. 그러므로 cyclin의 발현을 예후인자로 평가하기위해서는 많은 증례를 통한 장기간의 추적관찰을 통한 생존율에 관한 연구가 됫받침 되어야 할 것으로 사료된다. Objective : Cyclins D1 and E play important roles in the progression of cell through G1 phase of the cell cycle. Amplification and/or overexpression of the cyclin D1 gene and aberrant expression of cyclin E has been described in various forms of human cancer. However, the role of cyclins D1 and E in endometrial cancer has been poorly defined. Methods : We examined the expression of cyclins D1 and E by Northern blot technique in 33 endometrial carcinoma specimens and 9 control endometrial tissues. In addition, expression of the estrogen and progesterone receptors (ER, PR) was studied by enzyme immunoassay to explore the relationship between cyclins D1 and E and endometrial cancer. Results : We found that cyclin D1 expression showed down-regulated expression in endometrial cancer. Underexpression of cyclin D1 inversely related with ER positivity. However, cyclin E expression was increased in ER positive cancer group. Other clinicopathological prognostic factors were not correlated with cyclins D1 and E expression. Conclusion : Further study based on larger numbers of cases with correlation of cyclins D1 and E status and survival data will be needed to elucidate the use of cyclin expressions as prognostic factor.

갑상선유두암에서 p53과 Cyclin D1의 발현이 가지는 예후인자로서의 의미

류정원(Jung Won Ryu),이영돈(Young Don Lee),정유승(Yoo Seung Chung),정동해(Dong Hae Chung),석재연(Jae Yeon Seok) 대한갑상선-내분비외과학회 2015 The Koreran journal of Endocrine Surgery Vol.15 No.2

Purpose: P53 and cyclin D1 have been evaluated as a prognostic marker in papillary thyroid carcinoma (PTC). However, the relationship between p53/cyclin D1 and PTC prognosis has not yet been confirmed. Therefore, we investigated the relationship between p53/cyclin D1 and PTC prognostic factors. Methods: 919 patients with PTC were enrolled. Immunohistochemistry slides were reviewed for p53 and cyclin D1 immunoreactivity. Patients were classified into two groups according to the p53 and cyclin D1 grade: negative for ≤5% and positive for >5%. Medical records were reviewed to evaluate the prognostic factors, lymph node metastatic ratio (LNMR), and MACIS score. We analyzed patients based on p53/cyclin D1(−/−), p53/cyclin D1(−/+), p53/cyclin D1(+/−), p53/cyclin D1(+/+) separately for evaluation of independent effect of p53 and cyclin D1. Results: Mean age of the patients was 49.73 years (range 15∼87), and tumor size was 1.19 cm (range 0.1∼5.0). P53 was positive in 809 (88.0%) and cyclin D1 was positive in 748 (81.4%). Positivity of p53 and cyclin D1 were correlated (r=0.448). There was no statistical significance in MACIS score. Positivity of p53 and cyclin D1 were related with larger tumor size, older age, early T stage, more tumor capsulation, and female. LNMR was higher in p53/cyclin D1(+/−) than p53/cyclin D1(−/−) (P=0.036), p53/cyclin D1(−/+) than p53/cyclin D1(−/−) (P=0.034), and p53/cyclin D1(+/+) than p53/cyclin D1(−/−) (P=0.007). Conclusion: There was no consistent relationship between p53/cyclin D1 and worse prognostic factors of PTC. However, LNMR was higher in p53(+) and cyclin D1(+) cases independently, much more in p53/cyclin D1(+/+) than p53/cyclin D1(−/−).

위암환자의 예후인자로서 cyclin D1의 유용성에 관한 연구

류석용,김홍용,한세환,배병노 인제대학교 백병원 2002 仁濟醫學 Vol.23 No.1

■ Objectives This study was conducted to evaluate the clinical implication of cyclin D1 expression in human gastric cancer. In addition, clinical utility of cyclin D1 as a prognostic marker in human gastric cancer was also evaluated. ■ Methods and materials Medical records and archival pathology tissues from 76 primary gastric cancer patients who underwent curative gastric resection and same postoperative adjuvant chemotherapy were evaluated. Correlation between cyclin D1 expression and clinicopathological parameters was investigated. ■ Results Expression of cyclin D1 was observed in 22 of 76(28.9%) gastric cancer tissues. Expression of cyclin D1 did not correlate with depth of tumor infiltration(p=0.15), lymph node metastasis (p=0.54) and pathologic stage of the disease(p=0.45). Cyclin D1 expression slightly increased in intestinal type tumors. but there was not significant correlation between cyclin D1 expression and Lauren's classification(p=0.50). Increased expression of cyclin D1 was observed more frequently in the tumors with high levels of S-phase fraction but there was not a sign ficant correlation between expression of cyclin D1 and S-phase(p=0.14). Cyclin D1 expression increased in diploid cancers but the result showed no statistical significance(p=0.47). In the analysis for prognostic significance of cyclin D1 in gastric cancer, there was not significant correlation between clinical outcome of the patients and cyclin D1 expression (p=0.39). ■ Conclusions Cyclin D1 expression was not significant correlation with clinicopathologic characteristics, cell growth and differentiation in human gastric cancer and expression of cyclin D1 did not have prognostic significance. Additional study seems to be necessary to elucidate the clinical utility of cyclin D1 as a useful prognostic marker in human gastric cancer.

다발성골수종 환자에서 p53, MDM2, Cyclin D1 단백 발현의 임상적 유용성

장은아,현봉학,이기범,차영주 大韓血液學會 2000 大韓血液學會誌 Vol.35 No.3