Kegg Pathway: Cell cycle

KEGG ID: 04110

Reference Diagram

KEGG Diagram for Cell cycle

Rat

There are 93 IPI Records from this pathway found in Rattus norvegicus.

Location of Cell cycle proteins on Rat Genome

IPI Record Position
1: Anapc7_predicted 12:35328245-35354166
2: Bub1b 3:105064397-105115883
3: Bub1_predicted 3:115324492-115354721
4: Bub3 1:191129017-191159134
5: Ccna1 2:144275401-144286450
6: Ccna2 2:123062754-123068984
7: Ccnb1 2:31574601-31581786
8: Ccnb2 8:74892114-74906205
9: Ccnd1 1:205360031-205366632
10: Ccnd2 4:163523817-163546501
11: Ccnd3 :-
12: Ccne2_predicted 5:25032750-25042590
13: Ccnh 2:14179894-14200704
14: Cdc14a_predicted 2:212496599-212652805
15: Cdc14b_predicted 17:6397504-6444556
16: Cdc20 5:138913180-138916552
17: Cdc25a 8:114237591-114256002
18: Cdc25b 3:118893716-118903516
19: Cdc25c_predicted 18:27206174-27225801
20: Cdc27 10:93678781-93725987
21: Cdc2a 20:20018044-20044030
22: Cdc6_predicted 10:87684983-87697065
23: Cdc7_predicted 14:3422648-3441061
24: Cdk2 7:2000196-2008032
25: Cdk4 7:67016944-67018905
26: Cdk6 4:27362748-27618018
27: Cdk7 2:31500917-31525585
28: Cdkn1a 20:7379386-7385595
29: Cdkn1b 4:171841696-171846572
30: Cdkn1c 1:203836010-203837562
31: Cdkn2a 5:108908749-108916380
32: Cdkn2b 5:108941290-108945331
33: Cdkn2c 5:131012524-131017679
34: Cdkn2d :-
35: Chek1 8:37954322-37974748
36: Chek2 12:45933900-45965427
37: Crebbp 10:11598680-11724122
38: E2f1 3:145032716-145054799
39: Espl1_predicted 7:141048197-141074225
40: Fzr1_predicted 7:9816498-9829003
41: Gadd45a 4:96649941-96652243
42: Gsk3b 11:64284731-64428698
43: Hdac1_predicted 9:78410675-78411442
44: Hdac2 20:41160335-41186492
45: IPI00357966 3:147734622-147796630
46: IPI00360666 :-
47: IPI00361669 :-
48: IPI00369732 8:56895083-56994044
49: IPI00392971 :-
50: LOC298795 :-
51: Mad2l1_predicted 4:96380094-96391131
52: Mad2l2 5:165218362-165222828
53: Mcm2_predicted 4:122978030-122990974
54: Mcm3_predicted 9:19537321-19554800
55: Mcm4 11:87169914-87182886
56: Mcm5_predicted 19:13978701-13999887
57: Mcm6 13:41045690-41070856
58: Mcm7 12:17607250-17614508
59: Mdm2_predicted 7:56997925-57033380
60: Orc1l 5:129877948-129901675
61: Orc2l 9:57124293-57161308
62: Orc3l 5:51172243-51226662
63: Orc4l 3:29813262-29851852
64: Orc6l 19:23116888-23124657
65: Pcna 3:120008711-120012673
66: Pkmyt1_predicted 10:12982319-12993697
67: Plk1 1:181002895-181012444
68: Prkdc_predicted 11:86951766-87169228
69: Pttg1 10:28527431-28532831
70: Q2PYT4_RAT 3:10805164-10907156
71: Rb1 15:53828905-53961923
72: Rbl2 19:17045131-17092597
73: RGD1305854_predicted 4:22522505-22554536
74: RGD1561600_predicted 17:41160371-41167549
75: RGD1562456_predicted 2:58770777-58796906
76: Sfn_predicted 5:151475395-151480395
77: Smad2 18:73180290-73241713
78: Smad3 8:67803909-67952056
79: Smad4 18:70432832-70461485
80: Smc1l1 X:41503436-41547650
81: Smc1l2_predicted 7:123079155-123140105
82: Tgfb1 1:80894439-80910881
83: Tgfb2 13:102718703-102818939
84: Tgfb3 6:110173443-110195215
85: Tp53 10:56399668-56411149
86: Wee1 1:167769601-167788053
87: Xrn1_predicted 8:100936342-101124595
88: Ywhab 3:154926023-155140469
89: Ywhae 10:63072128-63109841
90: Ywhag 12:21859841-21888031
91: Ywhah 14:83448396-83457804
92: Ywhaq 6:41945769-41976123
93: Ywhaz 7:72283986-72306431

Mouse

There are 93 IPI Records from this pathway found in Mus musculus.

Location of Cell cycle proteins on Mouse Genome

IPI Record Position
1: Abl1 2:31511748-31626236
2: Anapc1 2:128301549-128378816
3: Anapc10 8:82607892-82675131
4: Anapc11 11:120414527-120424288
5: Anapc2 2:25094508-25107924
6: Anapc4 5:53122383-53154982
7: Anapc5 5:123048086-123081919
8: Anapc7 5:122683098-122705196
9: Atm 9:53201763-53296362
10: Bub1 2:127492562-127523301
11: Bub1b 2:118289708-118333032
12: Bub3 7:131351858-131359873
13: Ccna1 3:55133406-55142971
14: Ccna2 3:36756415-36763547
15: Ccnb1 13:101879935-101886160
16: Ccnb2 9:70206853-70220718
17: Ccnb3 X:6136607-6187895
18: Ccnd1 7:144739321-144749220
19: Ccnd2 6:127091327-127116667
20: Ccnd3 17:46968322-47062874
21: Ccne1 7:37806746-37816294
22: Ccne2 4:11118501-11131926
23: Ccnh 13:85662587-85686833
24: Cdc14a 3:116265849-116416027
25: Cdc14b 13:64204535-64284140
26: Cdc16 8:13757667-13781859
27: Cdc20 4:117930836-117935274
28: Cdc23 18:34756484-34776537
29: Cdc25a 9:109732985-109751296
30: Cdc25b 2:130878399-130889936
31: Cdc25c 18:34858971-34877482
32: Cdc27 11:104321691-104366479
33: Cdc2a 10:68731992-68748269
34: Cdc45l 16:18694015-18725535
35: Cdc6 11:98723979-98740032
36: Cdc7 5:107204624-107225357
37: Cdk2 10:128100893-128107961
38: Cdk4 10:126466564-126470344
39: Cdk6 5:3350318-3528231
40: Cdk7 13:101803575-101831184
41: Cdkn1a 17:28821439-28828386
42: Cdkn1b 6:134886110-134890000
43: Cdkn1c 7:143267730-143270386
44: Cdkn2c 4:109158808-109163607
45: Cdkn2d 9:21038861-21041429
46: Chek1 9:36458153-36476298
47: Chek2 5:111080319-111114435
48: Crebbp 16:3999276-4128632
49: Cul1 6:47383910-47455725
50: Dbf4 5:8403001-8428612
51: E2f1 2:154250848-154261333
52: E2f2 4:135444470-135468133
53: E2f3 13:29914040-29993528
54: Espl1 15:102124359-102152390
55: Fzr1 10:80770008-80781499
56: Gadd45a 6:66964674-66966985
57: Gadd45b 10:80333216-80335333
58: Gadd45g 13:51859174-51860968
59: Gsk3b 16:38008240-38165318
60: Hdac1 4:129018408-129045017
61: Hdac2 10:36663960-36691304
62: IPI00678029 :-
63: Mad1l1 5:140261163-140574024
64: Mad2l1 6:66465046-66470571
65: Mad2l2 4:146974720-146989496
66: Mcm2 6:88849641-88863163
67: Mcm3 1:20788124-20805411
68: Mcm4 16:15537479-15550936
69: Mcm5 8:78005641-78024177
70: Mcm6 1:130159137-130187210
71: Mcm7 5:138394377-138401650
72: Mdm2 10:117091888-117113704
73: Orc1l 4:108076996-108112768
74: Orc2l 1:58407317-58449473
75: Orc3l 4:34758190-34803831
76: Orc4l 2:48724861-48771243
77: Orc5l 5:21998314-22062182
78: Orc6l 8:88189896-88198175
79: Pcna 2:131940727-131944621
80: Pkmyt1 17:23454063-23464364
81: Plk1 7:121950586-121960987
82: Prkdc 16:15551467-15755813
83: Pttg1 11:43263685-43269674
84: Rb1 14:71929657-72059946
85: Rbl1 2:156837339-156895960
86: Rbl2 8:93960214-94013949
87: Rbx1 15:81293628-81301187
88: Sfn 4:132873099-132873845
89: Skp1a 11:52080260-52089443
90: Skp2 15:9040536-9066587
91: Smad2 18:76367274-76431096
92: Smad3 9:63444773-63556000
93: Smad4 :-
94: Smc1a X:147357144-147402683
95: Smc1b 15:84892453-84959723
96: Tfdp1 8:13338728-13378419
97: Tgfb1 7:25395762-25413756
98: Tgfb2 1:188324430-188406777
99: Tgfb3 12:86945904-86968101
100: Trp53 11:69396600-69407992
101: Wee1 7:109913527-109933289
102: Ywhab 2:163686638-163710028
103: Ywhae 11:75549134-75582033
104: Ywhag 5:136193038-136219180
105: Ywhah 5:33335738-33344822
106: Ywhaq 12:21636819-21663926
107: Ywhaz 15:36715359-36738833

Human

There are 93 IPI Records from this pathway found in Homo sapiens.

Location of Cell cycle proteins on Human Genome

IPI Record Position
1: ABL1 9:132579089-132752883
2: ANAPC1 2:112243113-112358212
3: ANAPC10 4:146135765-146238815
4: ANAPC11 17:77442895-77451655
5: ANAPC2 9:139189057-139202878
6: ANAPC4 4:24987933-25029218
7: ANAPC5 12:120230544-120274585
8: ANAPC7 12:109296332-109325815
9: ATM 11:107598769-107745036
10: ATR 3:143650773-143780341
11: BUB1 2:111111883-111152135
12: BUB1B 15:38240530-38300627
13: BUB3 10:124903783-124914876
14: CCNA1 13:35904495-35914972
15: CCNA2 4:122958002-122964505
16: CCNB1 5:68498593-68509828
17: CCNB2 15:57184612-57204535
18: CCNB3 X:49856156-50111649
19: CCND1 11:69165054-69178422
20: CCND2 12:4253199-4284777
21: CCND3 6:42010649-42124404
22: CCNE1 19:34994741-35007056
23: CCNE2 8:95961631-95976660
24: CCNH 5:86725838-86744592
25: CDC14A 1:100590540-100758420
26: CDC14B 9:98292344-98421933
27: CDC16 13:114018476-114056300
28: CDC2 10:62208107-62224616
29: CDC20 1:43597199-43601461
30: CDC23 5:137551259-137576918
31: CDC25A 3:48173674-48204805
32: CDC25B 20:3724401-3734757
33: CDC25C 5:137649168-137701943
34: CDC27 17:42552625-42621664
35: CDC45L 22:17847416-17888134
36: CDC6 17:35697672-35712939
37: CDC7 1:91739021-91763909
38: CDK2 12:54646826-54652832
39: CDK4 12:56428272-56432431
40: CDK6 7:92072175-92301148
41: CDK7 5:68566456-68609006
42: CDKN1A 6:36754413-36763094
43: CDKN1B 12:12761576-12766569
44: CDKN1C 11:2861019-2863577
45: CDKN2A 9:21957751-21984490
46: CDKN2B 9:21992902-21999312
47: CDKN2C 1:51199005-51212893
48: CDKN2D 19:10538139-10540655
49: CHEK1 11:125001547-125030847
50: CHEK2 22:27413731-27467822
51: CREBBP 16:3716572-3870723
52: CUL1 7:148058024-148129056
53: DBF4 7:87343480-87376792
54: E2F1 20:31727147-31737871
55: E2F2 1:23705509-23730300
56: E2F3 6:20510377-20601921
57: EP300 22:39817736-39905472
58: ESPL1 12:51948818-51973686
59: FZR1 19:3457368-3487191
60: GADD45A 1:67923332-67926609
61: GADD45B 19:2427135-2429257
62: GADD45G 9:91409748-91411290
63: GSK3B 3:121028238-121295954
64: HDAC1 1:32530274-32571823
65: HDAC2 6:114368571-114399029
66: LOC440917 2:138762069-138762767
67: MAD1L1 7:1821956-2236304
68: MAD2L1 4:121200029-121207411
69: MAD2L2 1:11657132-11674294
70: MCM2 3:128799943-128823964
71: MCM3 6:52236766-52257541
72: MCM4 8:49036047-49052621
73: MCM5 22:34126128-34150494
74: MCM6 2:136313674-136350481
75: MCM7 7:99528340-99537363
76: MDM2 12:67488247-67520481
77: ORC1L 1:52611089-52642719
78: ORC2L 2:201483140-201536655
79: ORC3L 6:88356562-88433883
80: ORC4L 2:148408202-148495606
81: ORC5L 7:103554026-103635731
82: ORC6L 16:45281059-45289806
83: PCNA 20:5043599-5055270
84: PKMYT1 16:2962795-2970475
85: PLK1 16:23597692-23609188
86: PRKDC 8:48848222-49035296
87: PTTG1 5:159781418-159788323
88: PTTG2 :-
89: RB1 13:47775912-47954123
90: RBL1 20:35058166-35157824
91: RBL2 16:52025862-52083060
92: RBX1 22:39677331-39698628
93: SFN 1:27062216-27063535
94: SKP1A 5:133520468-133540583
95: SKP2 5:36187946-36219902
96: SMAD2 18:43618435-43711221
97: SMAD3 15:65145249-65274586
98: SMAD4 18:46810611-46860142
99: SMC1A X:53417795-53466343
100: SMC1B 22:44118611-44188164
101: TFDP1 13:113287056-113343789
102: TGFB1 19:46528254-46551628
103: TGFB2 1:216586200-216684584
104: TGFB3 14:75494195-75517242
105: TP53 17:7512464-7531642
106: WEE1 11:9552057-9566725
107: YWHAB 20:42947731-42970587
108: YWHAE 17:1194558-1250231
109: YWHAG 7:75794053-75826252
110: YWHAH 22:30670447-30683587
111: YWHAQ 2:9641552-9688629
112: YWHAZ 8:102000090-102034745

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Recent Literature

Identification and characterization of novel ERC-55 interacting proteins: Evidence for the existence of several ERC-55 splicing variants; including the cytosolic ERC-55-C.

Proteomics. 2009 Nov 19;
Ludvigsen M, Jacobsen C, Maunsbach AB, Honoré B

ERC-55, encoded from RCN2, is localized in the ER and belongs to the CREC protein family. ERC-55 is involved in various diseases and abnormal Cell behavior, however, the function is not well defined and it has controversially been reported to interact with a cytosolic protein, the vitamin D receptor. We have used a number of proteomic techniques to further our functional understanding of ERC-55. By affinity purification, we observed interaction with a large variety of proteins, including those secreted and localized outside of the secretory pathway, in the cytosol and also in various organelles. We confirm the existence of several ERC-55 splicing variants including ERC-55-C localized in the cytosol in association with the cytoskeleton. Localization was verified by immunoelectron microscopy and sub-Cellular fractionation. Interaction of lactoferrin, S100P, calcyclin (S100A6), peroxiredoxin-6, kininogen and lysozyme with ERC-55 was further studied in vitro by SPR experiments. Interaction of S100P requires [Ca(2+)] of approximately 10(-7) M or greater, while calcyclin interaction requires [Ca(2+)] of >10(-5) M. Interaction with peroxiredoxin-6 is independent of Ca(2+). Co-localization of lactoferrin, S100P and calcyclin with ERC-55 in the perinuclear area was analyzed by fluorescence confocal microscopy. The functional variety of the interacting proteins indicates a broad spectrum of ERC-55 activities such as immunity, redox homeostasis, Cell cycle regulation and coagulation.

The novel ruthenium-gamma-linolenic complex [Ru(2)(aGLA)(4)Cl] inhibits C6 rat glioma Cell proliferation and induces changes in mitochondrial membrane potential, increased reactive oxygen species generation and apoptosis in vitro.

Cell Biochem Funct. 2009 Nov 19;
Ribeiro G, Benadiba M, de Oliveira Silva D, Colquhoun A

The present study reports the synthesis of a novel compound with the formula [Ru(2)(aGLA)4Cl] according to elemental analyses data, referred to as Ru(2)GLA. The electronic spectra of Ru(2)GLA is typical of a mixed valent diruthenium(II,III) carboxylate. Ru(2)GLA was synthesized with the aim of combining and possibly improving the anti-tumour properties of the two active components ruthenium and gamma-linolenic acid (GLA). The properties of Ru(2)GLA were tested in C6 rat glioma Cells by analysing Cell number, viability, lipid droplet formation, apoptosis, Cell cycle distribution, mitochondrial membrane potential and reactive oxygen species. Ru(2)GLA inhibited Cell proliferation in a time and concentration dependent manner. Nile Red staining suggested that Ru(2)GLA enters the Cells and ICP-AES elemental analysis found an increase in ruthenium from <0.02 to 425 mg/Kg in treated Cells. The sub-G1 apoptotic Cell population was increased by Ru(2)GLA (22 +/- 5.2%) when analysed by FACS and this was confirmed by Hoechst staining of nuclei. Mitochondrial membrane potential was decreased in the presence of Ru(2)GLA (44 +/- 2.3%). In contrast, the Cells which maintained a high mitochondrial membrane potential had an increase (18 +/- 1.5%) in reactive oxygen species generation. Both decreased mitochondrial membrane potential and increased reactive oxygen species generation may be involved in triggering apoptosis in Ru(2)GLA exposed Cells. The EC(50) for Ru(2)GLA decreased with increasing time of exposure from 285 microM at 24 h, 211 microM at 48 h to 81 microM at 72 h. In conclusion, Ru(2)GLA is a novel drug with antiproliferative properties in C6 glioma Cells and is a potential candidate for novel therapies in gliomas. Copyright (c) 2009 John Wiley & Sons, Ltd.

Regulation of ploidy and senescence by the AMPK-related kinase NUAK1.

EMBO J. 2009 Nov 19;
Humbert N, Navaratnam N, Augert A, Da Costa M, Martien S, Wang J, Martinez D, Abbadie C, Carling D, de Launoit Y, Gil J, Bernard D

Senescence is an irreversible Cell-cycle arrest that is elicited by a wide range of factors, including replicative exhaustion. Emerging evidences suggest that Cellular senescence contributes to ageing and acts as a tumour suppressor mechanism. To identify novel genes regulating senescence, we performed a loss-of-function screen on normal human diploid fibroblasts. We show that downregulation of the AMPK-related protein kinase 5 (ARK5 or NUAK1) results in extension of the Cellular replicative lifespan. Interestingly, the levels of NUAK1 are upregulated during senescence whereas its ectopic expression triggers a premature senescence. Cells that constitutively express NUAK1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator LATS1, whereas depletion of NUAK1 with shRNA exerts opposite effects. Interestingly, a dominant-negative form of LATS1 phenocopies NUAK1 effects. Moreover, we show that NUAK1 phosphorylates LATS1 at S464 and this has a role in controlling its stability. In summary, our work highlights a novel role for NUAK1 in the control of Cellular senescence and Cellular ploidy.

Xanthorrhizol, a Natural Sesquiterpenoid, Induces Apoptosis and Growth Arrest in HCT116 Human Colon Cancer Cells.

J Pharmacol Sci. 2009; 111(3): 276-284
Kang YJ, Park KK, Chung WY, Hwang JK, Lee SK

Xanthorrhizol is a sesquiterpenoid from the rhizome of Curcuma xanthorrhiza. In our previous studies, xanthorrhizol suppressed cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, inhibited cancer Cell growth, and exerted an anti-metastatic effect in an animal model. However, the exact mechanisms for its inhibitory effects against cancer Cell growth have not yet been fully elucidated. In the present study, we investigated the growth inhibitory effect of xanthorrhizol on cancer Cells. Xanthorrhizol dose-dependently exerted antiproliferative effects against HCT116 human colon cancer Cells. Xanthorrhizol also arrested Cell cycle progression in the G0/G1 and G2/M phase and induced the increase of sub-G1 peaks. Cell cycle arrest was highly correlated with the downregulation of cyclin A, cyclin B1, and cyclin D1; cyclin-dependent kinase 1 (CDK1), CDK2, and CDK4; proliferating Cell nuclear antigen; and inductions of p21 and p27, cyclin-dependent kinase inhibitors. The apoptosis by xanthorrhizol was markedly evidenced by induction of DNA fragmentation, release of cytochrome c, activation of caspases, and cleavage of poly-(ADP-ribose) polymerase. In addition, xanthorrhizol increased the expression and promoter activity of pro-apoptotic non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1). These findings provide one plausible mechanism for the growth inhibitory activity of xanthorrhizol against cancer Cells.

Molecular Time: An Often Overlooked Dimension to Cardiovascular Disease.

Circ Res. 2009 Nov 20; 105(11): 1047-1061
Martino TA, Sole MJ

Abstract: Diurnal rhythms influence cardiovascular physiology such as heart rate and blood pressure and the incidence of adverse cardiac events such as heart attack and stroke. For example, shift workers and patients with sleep disturbances, such as obstructive sleep apnea, have an increased risk of heart attack, stroke, and sudden death. Diurnal variation is also evident at the molecular level, as gene expression in the heart and blood vessels is remarkably different in the day as compared to the night. Much of the evidence presented here indicates that growth and renewal (structural remodeling) are highly dependent on processes that occur during the subjective night. Myocardial metabolism is also dynamic with substrate preference also differing day from night. The risk/benefit ratio of some therapeutic strategies and the appearance of biomarkers also vary across the 24-hour diurnal cycle. Synchrony between external and internal diurnal rhythms and harmony among the molecular rhythms within the Cell is essential for normal organ biology. Cell physiology is 4 dimensional; the substrate and enzymatic components of a given metabolic pathway must be present not only in the right compartmental space within the Cell but also at the right time. As a corollary, we show disrupting this integral relationship has devastating effects on cardiovascular, renal and possibly other organ systems. Harmony between our biology and our environment is vital to good health.

Correlation with Behavioral Activity and Rest Implies Circadian Regulation by SCN Neuronal Activity Levels.

J Biol Rhythms. 2009 Dec; 24(6): 477-487
Houben T, Deboer T, van Oosterhout F, Meijer JH

The SCN of the hypothalamus contains a major pacemaker, which exhibits 24-h rhythms in electrical impulse frequency. Although it is known that SCN electrical activity is high during the day and low during the night, the precise relationship between electrical activity and behavioral rhythms is almost entirely unknown. The authors performed long-term recordings of SCN multiple unit activity with the aid of implanted microelectrodes in parallel with the drinking activity in freely moving mice. The animals were kept in a 12h:12h light-dark cycle (LD 12:12) and in short-day (LD 8:16) and long-day photoperiods (LD 16:8). Onsets and offsets of behavioral activity occurred when SCN discharge was around half-maximum value. Of the onsets 80%, and of the offsets 62%, occurred when SCN electrical activity differed less than 15% from the half-maximum electrical activity levels. Transitions between rest and activity could be described by a sigmoid shaped probability curve with Hill coefficients of 7.0 for onsets and 5.7 for offsets. The similarity in the onset and offset levels shows an absence of hysteresis in the control of behavioral activity by the SCN. Exposure to short- or long-day photoperiods induced significant alterations in the waveform of electrical activity but did not affect SCN electrical activity levels at which behavioral transitions occurred. In all photoperiods, the SCN signal was skewed with more rapid discharge changes during onsets (19% per hour) than offsets (11% per hour). The precision of the circadian system appears optimized, as transitions between behavioral activity and rest occur when the change in SCN electrical activity is maximal, both during the declining and rising phase. The authors conclude that transitions in behavioral state can be described by a probability function around half-maximum electrical activity levels and that the parameters of the SCN, predicting onset and offset of behavior, are remarkably insensitive to environmental conditions.

Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment.

Endocr Relat Cancer. 2009 Nov 19;
Krishnan A, Feldman D

Calcitriol, the hormonally active form of vitamin D exerts multiple anti-proliferative and pro-differentiating effects including Cell cycle arrest and induction of apoptosis in many malignant Cells. It is currently being evaluated as an anti-cancer agent. Our recent research reveals that calcitriol also exhibits several anti-inflammatory effects. Calcitriol inhibits the synthesis and biological actions of pro-inflammatory prostaglandins (PGs) by three mechanisms: (i) suppression of the expression of Cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs, (ii) up-regulation of the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs and (iii) down-regulation of the expression of PG receptors that are essential for PG signaling. The combination of calcitriol and non-steroidal anti-inflammatory drugs (NSAIDs) results in a synergistic inhibition of the growth of prostate cancer (PCa) Cells and offers a potential therapeutic strategy for PCa. Calcitriol increases the expression of Mitogen-activated protein kinase phosphatase 5 (MKP5) in prostate Cells resulting in the subsequent inhibition of p38 stress kinase signaling and the attenuation of the production of pro-inflammatory cytokines. Calcitriol also exerts anti-inflammatory activity in PCa through the inhibition of NFkappaB signaling that results in potent anti-inflammatory and anti-angiogenic effects. Other important direct effects of calcitriol as well as the consequences of its anti-inflammatory effects include the inhibition of tumor angiogenesis, invasion and metastasis. We hypothesize that these anti-inflammatory actions, in addition to the other known anti-cancer effects of calcitriol, play an important role in its potential use for the prevention and treatment of PCa.

Per2 Is a C/EBP Target Gene Implicated in Myeloid Leukemia.

Integr Cancer Ther. 2009 Nov 18;
Gery S, Koeffler HP

Circadian rhythms are endogenous biological clocks that govern fundamental physiological and behavioral functions. Consequently, perturbations of these rhythms have been associated with pathogenic conditions, such as depression, diabetes, and cancer. CCAAT/enhancer-binding proteins (C/EBPs) are a family of transcription factors that regulate Cell growth and differentiation in various tissues and have also been implicated in many cancer types. Using expression profiling studies,we found that the levels of 2 core components of the circadian network, Per2 and Rev-Erbalpha,are significantly altered by C/EBPs. Further studies showed that levels of Per2 were reduced in lymphoma and acute myeloid leukemia patient samples, as well as in lymphoma Cell lines. Overexpression of Per2 in hematopoietic cancer Cell lines resulted in growth inhibition, Cell cycle arrest, apoptosis and loss of clonogenic ability. These results support the emerging role of circadian genes in tumor suppression.

Effect of the anti-neoplastic drug doxorubicin on XPD-mutated DNA repair-deficient human Cells.

DNA Repair (Amst). 2009 Nov 16;
Saffi J, Agnoletto MH, Guecheva TN, Batista LF, Carvalho H, Henriques JA, Stary A, Menck CF, Sarasin A

Doxorubicin (DOX), a member of the anthracycline group, is a widely used drug in cancer therapy. The mechanisms of DOX action include topoisomerase II-poisoning, free radical release, DNA adducts and interstrand cross-link (ICL) formation. Nucleotide excision repair (NER) is involved in the removal of helix-distorting lesions and chemical adducts, however, little is known about the response of NER-deficient Cell lines to anti-tumoral drugs like DOX. Wild type and XPD-mutated Cells, harbouring mutations in different regions of this gene and leading to XP-D, XP/CS or TTD diseases, were treated with this drug and analyzed for Cell cycle arrest and DNA damage by comet assay. The formation of DSBs was also investigated by determination of gammaH2AX foci. Our results indicate that all three NER-deficient Cell lines tested are more sensitive to DOX treatment, when compared to wild type Cells or XP Cells complemented by the wild type XPD cDNA, suggesting that NER is involved in the removal of DOX-induced lesions. The Cell cycle analysis showed the characteristic G2 arrest in repair-proficient MRC5 Cell line after DOX treatment, whereas the repair-deficient Cell lines presented significant increase in sub-G1 fraction. The NER-deficient Cell lines do not show different patterns of DNA damage formation as assayed by comet assay and phosphorylated H2AX foci formation. Knock-down of topoisomerase IIalpha with siRNA leads to increased survival in both MRC5 and XP Cells, however, XP Cell line still remained significantly more sensitive to the treatment by DOX. Our study suggests that the enhanced sensitivity is due to DOX-induced DNA damage that is subject to NER, as we observed decreased unscheduled DNA synthesis in XP-deficient Cells upon DOX treatment. Furthermore, the complementation of the XPD-function abolished the observed sensitivity at lower DOX concentrations, suggesting that the XPD helicase activity is involved in the repair of DOX-induced lesions.

Healthy clocks, healthy body, healthy mind.

Trends Cell Biol. 2009 Nov 16;
Reddy AB, O'Neill JS

Circadian rhythms permeate mammalian biology. They are manifested in the temporal organisation of behavioural, physiological, Cellular and neuronal processes. Whereas it has been shown recently that these approximately 24-hour cycles are intrinsic to the Cell and persist in vitro, internal synchrony in mammals is largely governed by the hypothalamic suprachiasmatic nuclei that facilitate anticipation of, and adaptation to, the solar cycle. Our timekeeping mechanism is deeply embedded in Cell function and is modelled as a network of transcriptional and/or post-translational feedback loops. Concurrent with this, we are beginning to understand how this ancient timekeeper interacts with myriad Cell systems, including signal transduction cascades and the Cell cycle, and thus impacts on disease. An exemplary area where this knowledge is rapidly expanding and contributing to novel therapies is cancer, where the Period genes have been identified as tumour suppressors. In more complex disorders, where aetiology remains controversial, interactions with the clockwork are only now starting to be appreciated.

Temperature sensitivity on growth and/or replication of H1N1, H1N2 and H3N2 influenza A viruses isolated from pigs and birds in mammalian Cells.

Vet Microbiol. 2009 Oct 28;
Massin P, Kuntz-Simon G, Barbezange C, Deblanc C, Oger A, Marquet-Blouin E, Bougeard S, van der Werf S, Jestin V

Influenza A viruses have been isolated from a wide range of animal species, aquatic birds being the reservoir for their genetic diversity. Avian influenza viruses can be transmitted to humans, directly or indirectly through an intermediate host like pig. This study aimed to define in vitro conditions that could prove useful to evaluate the potential of influenza viruses to adapt to a different host. Growth of H1N1, H1N2 and H3N2 influenza viruses belonging to different lineages isolated from birds or pigs prior to 2005 was tested on MDCK or NPTr Cell lines in the presence or absence of exogenous trypsin. Virus multiplication was compared at 33, 37 and 40 degrees C, the infection site temperatures in human, swine and avian hosts, respectively. Temperature sensitivity of PB2-, NP- and M-RNA replication was also tested by quantitative real-time PCR. Multiplication of avian viruses was cold-sensitive, whatever Cell type. By contrast, temperature sensitivity of swine viruses was found to depend on the virus and the host Cell: for an H1N1 swine isolate from 1982, multiplication was cold-sensitive on NPTr Cells and undetectable at 40 degrees C. From genetic analyses, it appears that temperature sensitivity could involve other residues than PB2 residue 627 and could affect other steps of the replication cycle than replication.

Control of the G2/M checkpoints after exposure to low doses of ionising radiation: Implications for hyper-radiosensitivity.

DNA Repair (Amst). 2009 Nov 17;
Fernet M, Mégnin-Chanet F, Hall J, Favaudon V

Two molecularly distinct G2/M Cell cycle arrests are induced after exposure to ionising radiation (IR) depending on the Cell cycle compartment in which the Cells are irradiated. The aims of this study were to determine whether there are threshold doses for their activation and investigate the molecular pathways and possible links between the G2 to M transition and hyper-radiosensitivity (HRS). Two human glioblastoma Cell lines (T98G-HRS(+) and U373-HRS(-)) unsynchronized or enriched in G2 were irradiated and flow cytometry with BrdU or histone H3 phosphorylation analysis used to assess Cell cycle progression and a clonogenic assay to measure radiation survival. The involvement of ATM, Wee1 and PARP was studied using chemical inhibitors. We found that Cells irradiated in either the G1 or S phase of the Cell cycle transiently accumulate in G2 in a dose-dependent manner after exposure to doses as low as 0.2Gy. Only Wee1 inhibition reduced this G2 accumulation. A block of the G2 to M transition was found after irradiation in G2 but occurs only above a threshold dose, which is Cell line dependent, and requires ATM activity after exposure to doses above 0.5Gy. A failure to activate this early G2/M checkpoint correlates with low dose radiosensitization. These results provide evidence that after exposure to low doses of IR two distinct G2/M checkpoints are activated, each in a dose-dependent manner, with distinct threshold doses and involving different damage signalling pathways and confirm links between the early G2/M checkpoint and hyper-radiosensitivity.

Static magnetic fields aggravate the effects of ionizing radiation on Cell cycle progression in bone marrow stem Cells.

Micron. 2009 Oct 24;
Sarvestani AS, Abdolmaleki P, Mowla SJ, Ghanati F, Heshmati E, Tavasoli Z, Jahromi AM

In order to evaluate the influence of static magnetic fields (SMF) on the progression of Cell cycle as a monitor of presumptive genotoxicity of these fields, the effects of a 15mT SMF on Cell cycle progression in rat bone marrow stem Cells (BMSC) were examined. The Cells were divided into two groups. One group encountered SMF alone for 5h continuously but the other group exposed with X ray before treatment with SMF. The population of Cells did not show any significant difference in the first group but the second group that was exposed with acute radiation before encountering SMF showed a significant increase in the number of Cells in G(2)/M phase. So SMF has intensified the effects of X ray, where SMF alone, did not had any detectable influence on Cell cycle. These findings suggest that magnetic fields (MF) play their role by increasing the effects of genotoxic agents and because of the greater concentration of free radicals in the presence of radical pair producers, this effect is better detectable.

Induction of G1 Cell cycle arrest and mitochondria-mediated apoptosis in MCF-7 human breast carcinoma Cells by selenium-enriched Spirulina extract.

Biomed Pharmacother. 2009 Oct 27;
Chen T, Wong YS, Zheng W

Both selenium (Se) and Spirulina have been demonstrated to show anticancer potential. In the present study, we showed that Se-enriched Spirulina platensis extract (Se-SE) inhibited the growth of MCF-7 human breast cancer Cells through induction of G1 Cell cycle arrest and mitochondria-mediated apoptosis. Se-SE-induced G1-phase arrest was associated with a decrease in expressions of cyclin D1, cyclin D3, CDK4 and CKD6, and an increase in protein levels of p15 INK4B, p21 Waf1/Cip1 and p53. Induction of apoptosis by Se-SE was evidenced by accumulation of sub-G1 Cell population, DNA fragmentation and nuclear condensation. This apoptotic process was accompanied by the activation of caspase-8 and caspase-9 and PARP cleavage. Moreover, Se-SE-induced mitochondrial dysfunction through up-regulation of Bax and Bad expression and down-regulation of Bcl-xl expression. Our results suggest the potential applications of Se-SE in chemoprevention of human breast cancer.

Influence of TEGDMA on the mammalian Cell cycle in comparison with chemotherapeutic agents.

Dent Mater. 2009 Nov 17;
Eckhardt A, Müller P, Hiller KA, Krifka S, Bolay C, Spagnuolo G, Schmalz G, Schweikl H

OBJECTIVES: The dental resin monomer triethylene glycol dimethacrylate (TEGDMA) caused a Cell cycle arrest in response to DNA damage. However, the underlying mechanisms are unclear. Therefore, the influence of TEGDMA on the Cell cycle was analyzed in comparison with the chemotherapeutic agents adriamycin and mitomycin C (MMC), which arrest the Cell cycle through different mechanisms. METHODS: RAW264.7 mouse macrophages were exposed to TEGDMA, adriamycin, or MMC, and flow cytometry (FACS) was used for Cell cycle analyses. In addition, the number of surviving Cells was determined by a crystal violet assay, and viability in treated cultures was determined by FACS after staining of Cells with trypan blue. Morphological changes in Cells were interpreted using forward and side scatter (FSC/SSC) Cell physical criteria. RESULTS: The exposure of Cells to 1mM TEGDMA resulted in a delay of the Cell cycle in G1 phase since 85.3% of the Cells were found in G1 compared with 47.4% in untreated controls. Adriamycin also increased the number of Cells (72.1%) in G1 compared to controls. Caffeine, an inhibitor of the checkpoint kinases ATM (ataxia telangiectasia-mutated) and ATR (ATM and Rad3-related), had no effect on the TEGDMA and adriamycin-induced Cell cycle arrest. In contrast, MMC delayed the Cell cycle in G2 since Cell numbers increased to 22.1% compared to 10.7% in controls. The effect of MMC on G2 was even increased by low caffeine concentrations (100-400muM), but 1000muM caffeine inhibited MMC activity. SIGNIFICANCE: Our results suggest that the mechanism of a TEGDMA-induced arrest of the Cell cycle is different from the effect of the direct-acting interstrand crosslinking agent MMC. Since TEGDMA produced oxidative stress, it probably acts indirectly on the Cell cycle through reactive oxygen species, unless TEGDMA-DNA adducts are shown experimentally.

MiR-320 and miR-494 affect Cell cycles of primary murine bronchial epithelial Cells exposed to benzo[a]pyrene.

Toxicol In Vitro. 2009 Nov 16;
Duan H, Jiang Y, Zhang H, Wu Y

MicroRNAs (miRNAs) are a class of small noncoding RNA molecules with profound impact on various biological processes. Some miRNAs are involved in tumorigenesis by regulation of Cell cycle progression. Here, we cultured primary murine bronchial epithelial Cells and then examined the expression of miR-320 and miR-494 in Cells exposed to benzo[a]pyrene (B[a]P). To better characterize roles of miR-320 and miR-494 in Cell cycle progression, we used miRNA inhibitors to downregulate expression of miRNAs and determined Cell cycle distribution and expression of cyclin-dependent kinases 6 (CDK6) by flow cytometric analysis. Treating Cells with 1 muM B[a]P for 24 h resulted in time-dependent increases in miR-320 and miR-494 expression. Moreover, G1 arrest and downregulated expression of CDK6 were shown in the treated Cells. Flow cytometric analysis indicated a relief of G1 arrest and an elevated expression of CDK6 after inhibition of the expressions of miR-320 and miR-494 in Cells exposed to B[a]P. These results suggest that expression levels of miRNA-320 and miR-494, which regulate B[a]P-exposed Cell cycle progression, may impact G1/S transition through CDK6, and provide further insights into functions of miRNAs in Cell cycle of primary murine bronchial epithelial Cells exposed to B[a]P.

Viral and host proteins involved in picornavirus life cycle.

J Biomed Sci. 2009 Nov 20; 16(1): 103
Lin JY, Chen TC, Weng KF, Chang SC, Chen LL, Shih SR

ABSTRACT: Picornaviruses cause several diseases, not only in humans but also in various animal hosts. For instance, human enteroviruses can cause hand-foot-and-mouth disease, herpangina, myocarditis, acute flaccid paralysis, acute hemorrhagic conjunctivitis, severe neurological complications, including brainstem encephalitis, meningitis and poliomyelitis, and even death. The interaction between the virus and the host is important for viral replication, virulence and pathogenicity. This article reviews studies of the functions of viral and host factors that are involved in the life cycle of picornavirus. The interactions of viral capsid proteins with host Cell receptors is discussed first, and the mechanisms by which the viral and host Cell factors are involved in viral replication, viral translation and the switch from translation to RNA replication are then addressed. Understanding how Cellular proteins interact with viral RNA or viral proteins, as well as the roles of each in viral infection, will provide insights for the design of novel antiviral agents based on these interactions.

Expression profiling of rainbow trout testis development identifies evolutionary conserved genes involved in spermatogenesis.

BMC Genomics. 2009 Nov 20; 10(1): 546
Rolland AD, Lareyre JJ, Goupil AS, Monfort J, Ricordel MJ, Esquerre D, Hugot K, Houlgatte R, Chalmel F, Le Gac FF

ABSTRACT: BACKGROUND: Spermatogenesis is a late developmental process that involves a coordinated expression program in germ Cells and a permanent communication between the testicular somatic Cells and the germ-line. Current knowledge regarding molecular factors driving male germ Cell proliferation and differentiation in vertebrates is still limited and mainly based on existing data from rodents and human. Fish with a marked reproductive cycle and a germ Cell development in synchronous cysts have proven to be choice models to study precise stages of the spermatogenetic development and the germ Cell-somatic Cell communication network. In this study we used 9K cDNA microarrays to investigate the expression profiles underlying testis maturation during the male reproductive cycle of the trout, Oncorhynchus mykiss. RESULTS: Using total testis samples at various developmental stages and isolated spermatogonia, spermatocytes and spermatids, 3379 differentially expressed trout cDNAs were identified and their gene activation or repression patterns throughout the reproductive cycle were reported. We also performed a tissue-profiling analysis and highlighted many genes for which expression signals were restricted to the testes or gonads from both sexes. The search for orthologous genes in genome-sequenced fish species and the use of their mammalian orthologs allowed us to provide accurate annotations for trout cDNAs. The analysis of the GeneOntology terms therefore validated and broadened our interpretation of expression clusters by highlighting enriched functions that are consistent with known sequential events during male gametogenesis. Furthermore, we compared expression profiles of trout and mouse orthologs and identified a complement of genes for which expression during spermatogenesis was maintained throughout evolution. CONCLUSION: A comprehensive study of gene expression and associated functions during testis maturation and germ Cell differentiation in the rainbow trout is presented. The study identifies new pathways involved during spermatogonia self-renewal or rapid proliferation, meiosis and gamete differentiation, in fish and potentially in all vertebrates. It also provides the necessary basis to further investigate the hormonal and molecular networks that trigger puberty and annual testicular recrudescence in seasonally breeding species.

How meristem plasticity in response to soil nutrients and light affects plant growth in four Festuca grass species.

New Phytol. 2009 Nov 19;
Sugiyama SI, Gotoh M

New Phytologist (2009)Summary *Investigation of responses of meristems to environmental conditions is important for understanding the mechanisms and consequences of plant phenotypic plasticity. Here, we examined how meristem plasticity to light and soil nutrients affected leaf growth and relative growth rate (RGR) in fast- and slow-growing Festuca grass species. *Activity in shoot apical meristems was measured by leaf appearance rate, and that in leaf meristems by the duration and rate of Cell production, which was further divided into single Cell cycle time and the number of dividing Cells. *Light and soil nutrients affected activity in shoot apical meristems similarly. The high nutrient supply increased the number of dividing Cells, which was responsible for enhancement of Cell production rate; shaded conditions extended the duration of Cell production. As a result, leaf length increased under high nutrient and shaded conditions. The RGR was correlated positively with the total meristem size of the shoot under a low nutrient supply, implying inhibition of RGR by Cell production under nutrient-limited conditions. Fast-growing species were more plastic for Cell production rate and specific leaf area (SLA) but less plastic for RGR than slow-growing species. *This study demonstrates that meristem plasticity plays key roles in characterizing environmental responses of plant species.

Nuclear protein kinases: still enigmatic components in plant Cell signalling.

New Phytol. 2009 Nov 17;
Dahan J, Wendehenne D, Ranjeva R, Pugin A, Bourque S

New Phytologist (2009)Contents Summary1I. Introduction2II. Features of plant protein kinases2III. Nuclear protein kinases4IV. Nuclear PKs in the control of the Cell cycle and mitosis7V. Nuclear calcium-dependent protein kinases8VI. Nucleus-localized MAPKs 8VII. Nuclear protein kinases: cytosolic translocation of an activated form or activation in the nucleus? 9VIII. Concluding remarks11Acknowledgements11References11 Summary Plants constantly face changing conditions in their environment. Unravelling the transduction mechanisms from signal perception at the plasma membrane level down to gene expression in the nucleus is a fascinating challenge. Protein phosphorylation, catalysed by protein kinases, is one of the major posttranslational modifications involved in the specificity, kinetic(s) and intensity of a signal transduction pathway. Although commonly assumed, the involvement of nuclear protein kinases in signal transduction is often poorly characterized. In particular, both their regulation and mode of action remain to be elucidated and may lead to the unveiling of new original mechanisms. For example, unlike animal Cells, plant Cells contain only a few strictly nucleus-localized protein kinases, which calls into question the role of this Cellular distribution between the cytosol and the nucleus in their activation and functions. The control of their nucleocytoplasmic trafficking appears to play a major role in their regulation, probably through promoting interactions with their substrates under specific Cellular conditions. However, recent findings showing that the nucleus can generate complex networks of second messengers (e.g. Ca(2+)or diacyglycerol) suggest that nuclear protein kinases could play an active role in the decoding of such signals.