scholarly journals Cyclin D1: A Golden Gene in Cancer, Cardiotoxicity, and Cardioprotection

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Habib Haybar ◽  
Mehhdi Shahrouzian ◽  
Zahra Gatavizadeh ◽  
Najmaldin Saki ◽  
Mahmood Maniati ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Poor Prognosis ◽  
Therapeutic Response ◽  
Single Injection ◽  
Cdk Inhibitors ◽  
Cyclin D ◽  
Cyclin Dependent Kinase ◽  
Hypertrophic Growth ◽  
Cardiac System ◽  
Treatment Responses

Objective: Cyclin D1 is an essential protein that acts as a mitogenic sensor. In this manuscript, we discuss the importance of cyclin D1 in oncology and cardio-oncology, and we challenge the prognostic and therapeutic response values of cyclin D1 to figure out if it can be a beneficial marker. We also discuss the agents and microRNAs that can be used as a potential therapeutic approach via regulating cyclin D1 expression in oncology and cardio-oncology. Discussion: Clinical significance of cyclin D1 is defined not only in several cancers such as breast cancer, melanoma, and glioblastoma but also in cardiomyocyte regeneration and cardiac hypertrophic growth. Several studies have indicated that the injection of cardiotoxic agents such as doxorubicin (DOX) induces damage to the cardiac system and increases cyclin D expression at single injection, which might be related to DXO-mediated damage in the adult heart. However, cyclin D1 overexpression leads to hypertrophic growth of cardiomyocytes, and cyclin-dependent kinase (CDK)) inhibitors such as p16 do not inhibit the hypertrophic growth of cardiomyocytes. Thus, the reaction is CDK-independent. Conclusions: Cyclin D1 overexpression is positively correlated with tumor progression, treatment response, cardiotoxicity, and poor prognosis. Cyclin D1 expression has an important role in cardiac hypertrophy, and it can be a promising marker in monitoring cardiomyocyte treatment responses, cardioprotection, and cardiotoxicity. Finally, cyclin D1 plays an important role in hypertrophic growth of cardiomyocytes via a novel mechanism. Given all these pieces of evidence, cyclin D1 can be introduced as a favorable biomarker in future cardiology and cardio-oncology.

scholarly journals D-type cyclin-dependent kinase activity in mammalian cells.

1994 ◽  
Vol 14 (3) ◽  
pp. 2066-2076 ◽  
Author(s):  
H Matsushime ◽  
D E Quelle ◽  
S A Shurtleff ◽  
M Shibuya ◽  
C J Sherr ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mammalian Cells ◽  
Kinase Activity ◽  
Cyclin D3 ◽  
Tween 20 ◽  
Cyclin D ◽  
Cyclin Dependent Kinase ◽  
Proliferating Cells ◽  
Quiescent Cells ◽  
Serum Stimulation

D-type cyclin-dependent kinase activities have not so far been detected in mammalian cells. Lysis of rodent fibroblasts, mouse macrophages, or myeloid cells with Tween 20 followed by precipitation with antibodies to cyclins D1, D2, and D3 or to their major catalytic partner, cyclin-dependent kinase 4 (cdk4), yielded kinase activities in immune complexes which readily phosphorylated the retinoblastoma protein (pRb) but not histone H1 or casein. Virtually all cyclin D1-dependent kinase activity in proliferating macrophages and fibroblasts could be attributed to cdk4. When quiescent cells were stimulated by growth factors to enter the cell cycle, cyclin D1-dependent kinase activity was first detected in mid G1, reached a maximum near the G1/S transition, and remained elevated in proliferating cells. The rate of appearance of kinase activity during G1 phase lagged significantly behind cyclin induction and correlated with the more delayed accumulation of cdk4 and formation of cyclin D1-cdk4 complexes. Thus, cyclin D1-associated kinase activity was not detected during the G0-to-G1 transition, which occurs within the first few hours following growth factor stimulation. Rodent fibroblasts engineered to constitutively overexpress either cyclin D1 alone or cyclin D3 together with cdk4 exhibited greatly elevated cyclin D-dependent kinase activity, which remained absent in quiescent cells but rose to supraphysiologic levels as cells progressed through G1. Therefore, despite continued enforced overproduction of cyclins and cdk4, the assembly of cyclin D-cdk4 complexes and the appearance of their kinase activities remained dependent upon serum stimulation, indicating that upstream regulators must govern formation of the active enzymes.

scholarly journals Genetic Evidence for Functional Dependency of p18Ink4c on Cdk4

2004 ◽  
Vol 24 (15) ◽  
pp. 6653-6664 ◽  
Author(s):  
Xin-Hai Pei ◽  
Feng Bai ◽  
Tateki Tsutsui ◽  
Hiroaki Kiyokawa ◽  
Yue Xiong
Keyword(s):  
Double Mutant ◽  
Wide Spectrum ◽  
Genetic Evidence ◽  
Mutant Mice ◽  
Cdk Inhibitors ◽  
Cyclin D ◽  
Cyclin Dependent Kinase ◽  
Single Mutant ◽  
Cell Growth And Proliferation ◽  
Deficient Mice

ABSTRACT The INK4 family of cyclin-dependent kinase (CDK) inhibitors negatively regulates cyclin D-dependent CDK4 and CDK6 and induces the growth-suppressive function of Rb family proteins. Mutations in the Cdk4 gene conferring INK4 resistance are associated with familial and sporadic melanoma in humans and result in a wide spectrum of tumors in mice, suggesting that INK4 is a major regulator of CDK4. Mice lacking the Cdk4 gene exhibit various defects in many organs associated with hypocellularity, whereas loss of the p18 Ink4c gene results in widespread hyperplasia and organomegaly. To genetically test the notion that the function of INK4 is dependent on CDK4, we generated p18; Cdk4 double-mutant mice and examined the organs and tissues which developed abnormalities when either gene is deleted. We show here that, in all organs we have examined, including pituitary, testis, pancreas, kidney, and adrenal gland, hyperproliferative phenotypes associated with p18 loss were canceled. The double-mutant mice exhibited phenotypes very close to or indistinguishable from that of Cdk4 single-mutant mice. Mice lacking p27 Kip1 develop widespread hyperplasia and organomegaly similar to those developed by p18-deficient mice. The p27; Cdk4 double-mutant mice, however, displayed phenotypes intermediate between those of p27 and Cdk4 single-mutant mice. These results provide genetic evidence that in mice p18 Ink4c and p27 Kip1 mediate the transduction of different cell growth and proliferation signals to CDK4 and that p18 Ink4c is functionally dependent on CDK4.

scholarly journals Haploinsufficiency of p18INK4c Sensitizes Mice to Carcinogen-Induced Tumorigenesis

2003 ◽  
Vol 23 (4) ◽  
pp. 1269-1277 ◽  
Author(s):  
Feng Bai ◽  
Xin-Hai Pei ◽  
Virginia L. Godfrey ◽  
Yue Xiong
Keyword(s):  
Wide Spectrum ◽  
Tumor Development ◽  
Pituitary Tumors ◽  
Cdk Inhibitors ◽  
Cyclin D ◽  
Wild Type Allele ◽  
Cyclin Dependent Kinase ◽  
Loss Of Function ◽  
Wild Type ◽  
Targeted Deletion

ABSTRACT The INK4 family of cyclin-dependent kinase (CDK) inhibitors negatively regulates cyclin D-dependent CDK4 and CDK6 and thereby retains the growth-suppressive function of Rb family proteins. Mutations in the CDK4 gene conferring INK4 resistance are associated with familial and sporadic melanoma in humans and result in a wide spectrum of tumors in mice. Whereas loss of function of other INK4 genes in mice leads to little or no tumor development, targeted deletion of p18 INK4c causes spontaneous pituitary tumors and lymphoma late in life. Here we show that treatment of p18 null and heterozygous mice with a chemical carcinogen resulted in tumor development at an accelerated rate. The remaining wild-type allele of p18 was neither mutated nor silenced in tumors derived from heterozygotes. Hence, p18 is a haploinsufficient tumor suppressor in mice.

D-type cyclin-dependent kinase activity in mammalian cells

1994 ◽  
Vol 14 (3) ◽  
pp. 2066-2076
Author(s):  
H Matsushime ◽  
D E Quelle ◽  
S A Shurtleff ◽  
M Shibuya ◽  
C J Sherr ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mammalian Cells ◽  
Kinase Activity ◽  
Cyclin D3 ◽  
Tween 20 ◽  
Cyclin D ◽  
Cyclin Dependent Kinase ◽  
Proliferating Cells ◽  
Quiescent Cells ◽  
Serum Stimulation

D-type cyclin-dependent kinase activities have not so far been detected in mammalian cells. Lysis of rodent fibroblasts, mouse macrophages, or myeloid cells with Tween 20 followed by precipitation with antibodies to cyclins D1, D2, and D3 or to their major catalytic partner, cyclin-dependent kinase 4 (cdk4), yielded kinase activities in immune complexes which readily phosphorylated the retinoblastoma protein (pRb) but not histone H1 or casein. Virtually all cyclin D1-dependent kinase activity in proliferating macrophages and fibroblasts could be attributed to cdk4. When quiescent cells were stimulated by growth factors to enter the cell cycle, cyclin D1-dependent kinase activity was first detected in mid G1, reached a maximum near the G1/S transition, and remained elevated in proliferating cells. The rate of appearance of kinase activity during G1 phase lagged significantly behind cyclin induction and correlated with the more delayed accumulation of cdk4 and formation of cyclin D1-cdk4 complexes. Thus, cyclin D1-associated kinase activity was not detected during the G0-to-G1 transition, which occurs within the first few hours following growth factor stimulation. Rodent fibroblasts engineered to constitutively overexpress either cyclin D1 alone or cyclin D3 together with cdk4 exhibited greatly elevated cyclin D-dependent kinase activity, which remained absent in quiescent cells but rose to supraphysiologic levels as cells progressed through G1. Therefore, despite continued enforced overproduction of cyclins and cdk4, the assembly of cyclin D-cdk4 complexes and the appearance of their kinase activities remained dependent upon serum stimulation, indicating that upstream regulators must govern formation of the active enzymes.

scholarly journals Cyclin-Dependent Kinase Regulatory Subunit 2 Indicated Poor Prognosis and Facilitated Aggressive Phenotype of Hepatocellular Carcinoma

2019 ◽  
Vol 2019 ◽  
pp. 1-13
Author(s):  
Jie Zhang ◽  
Qianqian Song ◽  
Jinxia Liu ◽  
Lina Lu ◽  
Yuqing Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Disease Free Survival ◽  
Normal Liver ◽  
Regulatory Subunit ◽  
Mrna Levels ◽  
Cyclin Dependent Kinase ◽  
Normal Tissues ◽  
Hcc Cells

Cyclin-dependent kinase regulatory subunit 2 (CKS2) is a member of the cell cycle-dependent protein kinase subunit family, which is implicated as an oncogene in various malignancies. However, the clinical significance, oncogenic functions, and related mechanisms of CKS2 in hepatocellular carcinoma (HCC) remain largely unclear. In the present study, expression features and prognostic value of CKS2 were evaluated in the bioinformatic databases and HCC tissues. The effects of CKS2 on the malignant phenotypes of HCC cells were explored in vitro. According to the analyses of three bioinformatic databases, mRNA levels of CKS2 were elevated in HCC tissues compared with the normal tissues. Immunohistochemical assays found that high CKS2 expression was closely associated with liver cirrhosis (P=0.019), poor differentiation (P=0.02), portal vein invasion (P<0.001), TNM stage (P=0.019), tumor metastasis (P=0.008), and recurrence (P=0.003). The multivariate regression analyses suggested that CKS2 was an independent prognostic factor for overall survival (HR=2.088, P=0.014) and disease-free survival (HR=2.511, P=0.002) of HCC patients. Moreover, the bioinformatic analyses indicated that CKS2 might be associated with the malignant phenotypes in HCC progression. In addition, in vitro assays showed that CKS2 expression was higher in HCC cell lines than in normal liver cells. Knockdown of CKS2 remarkably repressed the proliferation, colony formation (P=0.0003), chemoresistance, migration (P=0.0047), and invasion (P=0.0012) of HCC cells. Taken together, overexpression of CKS2 was significantly correlated with poor prognosis of HCC patients and the malignant phenotypes of HCC cells, suggesting that it was a novel prognostic biomarker and potential target of HCC.

scholarly journals Differential Regulation of Retinoblastoma Tumor Suppressor Protein by G1 Cyclin-Dependent Kinase Complexes In Vivo

2001 ◽  
Vol 21 (14) ◽  
pp. 4773-4784 ◽  
Author(s):  
Sergei A. Ezhevsky ◽  
Alan Ho ◽  
Michelle Becker-Hapak ◽  
Penny K. Davis ◽  
Steven F. Dowdy
Keyword(s):  
Cyclin E ◽  
Active Form ◽  
Dominant Negative ◽  
Tumor Suppressor Protein ◽  
Cyclin D ◽  
Cyclin Dependent Kinase ◽  
Retinoblastoma Tumor Suppressor Protein ◽  
Retinoblastoma Tumor Suppressor ◽  
Retinoblastoma Tumor

ABSTRACT The retinoblastoma tumor suppressor protein (pRB) negatively regulates early-G1 cell cycle progression, in part, by sequestering E2F transcription factors and repressing E2F-responsive genes. Although pRB is phosphorylated on up to 16 cyclin-dependent kinase (Cdk) sites by multiple G1 cyclin-Cdk complexes, the active form(s) of pRB in vivo remains unknown. pRB is present as an unphosphorylated protein in G0 quiescent cells and becomes hypophosphorylated (∼2 mol of PO4 to 1 mol of pRB) in early G1 and hyperphosphorylated (∼10 mol of PO4 to 1 mol of pRB) in late G1 phase. Here, we report that hypophosphorylated pRB, present in early G1, represents the biologically active form of pRB in vivo that is assembled with E2Fs and E1A but that both unphosphorylated pRB in G0 and hyperphosphorylated pRB in late G1 fail to become assembled with E2Fs and E1A. Furthermore, using transducible dominant-negative TAT fusion proteins that differentially target cyclin D-Cdk4 or cyclin D-Cdk6 (cyclin D-Cdk4/6) and cyclin E-Cdk2 complexes, namely, TAT-p16 and TAT–dominant-negative Cdk2, respectively, we found that, in vivo, cyclin D-Cdk4/6 complexes hypophosphorylate pRB in early G1 and that cyclin E-Cdk2 complexes inactivate pRB by hyperphosphorylation in late G1. Moreover, we found that cycling human tumor cells expressing deregulated cyclin D-Cdk4/6 complexes, due to deletion of the p16 INK4a gene, contained hypophosphorylated pRB that was bound to E2Fs in early G1and that E2F-responsive genes, including those for dihydrofolate reductase and cyclin E, were transcriptionally repressed. Thus, we conclude that, physiologically, pRB is differentially regulated by G1 cyclin-Cdk complexes.

Expression of cyclin D1 and CDK4 causes hypertrophic growth of cardiomyocytes in culture: a possible implication for cardiac hypertrophy

2002 ◽  
Vol 296 (2) ◽  
pp. 274-280 ◽  
Author(s):  
Mimi Tamamori-Adachi ◽  
Hiroshi Ito ◽  
Kiyoshi Nobori ◽  
Kentaro Hayashida ◽  
Junya Kawauchi ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cyclin D1 ◽  
Hypertrophic Growth

Cyclin Dl expression as a prognostic factor in advanced hypopharyngeal carcinoma

1998 ◽  
Vol 112 (6) ◽  
pp. 552-555 ◽  
Author(s):  
Goshi Nishimura ◽  
Mamoru Tsukuda ◽  
Li-Xin Zhou ◽  
Shigeru Furukawa ◽  
Yuh Baba
Keyword(s):  
Survival Rate ◽  
Cyclin D1 ◽  
Predictive Marker ◽  
Hypopharyngeal Carcinoma ◽  
Cyclin D ◽  
Clinical Factors ◽  
N Classification ◽  
Cyclin Dl ◽  
Positive Immunoreactivity ◽  
Neo Adjuvant Chemotherapy

AbstractHypopharyngeal carcinoma (HPC) has a poor prognosis. We investigated the expression of cyclin D1 in 34 advanced HPCs, and the value of cyclin D1 expression was evaluated as a predictive marker in terms of the prognosis of HPC, compared with other clinical factors. Using immunohistochemical staining, 20 of 34 patients showed positive immunoreactivity for cyclin D1. The statistical trend of the survival rate was lower in the cyclin Di-positive patients than in the cyclin D-negative ones (p = 0.0805). The predictive factors for the survival rate were effectiveness of neo-adjuvant chemotherapy (F = 8.698) (p = 0.0066), cyclin D1 expression (F = 6.244) (p = 0.0191) and N classification (F = 5.037) (p = 0.0335). The cyclin D1-positive patients had approximately four-fold higher mortality than the cyclin D1-negative ones. These data indicate that the expression of cyclin D1 in advanced patients with hypopharyngeal carcinoma is a useful marker for prognosis.

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