195:; however, the exact role of CIP/KIP proteins in cancer progression has been difficult to assess because a complete loss of CIP/KIP function has not been observed in any cancers. However, low-expression p27 has been observed in a wide variety of tumors and is associated with increased tumor aggression. In addition, p27 null mice spontaneously develop tumors in the pituitary gland and are more susceptible to chemical carcinogens or irradiation. In particular, not only the expression of p27, but also the subcellular localization of p27 is thought to play an important role in tumorigenesis. Elevated cytoplasmic localization of p27 has been observed in a number of cancers and has been associated with a poor prognosis. This mislocalization could potentially explain how p27 could simultaneously promote cell cycle progression and increased motility in cancers. A similar model could also be equally true of other CIP/KIP proteins.
115:
p27 would frequently immunoprecipitate with active cyclin D-CDK4 complexes. Futhurmore, mouse embryonic fibroblasts deficient for p21 and p27 had lower levels of cyclin D1 and immunoprecipitated cyclinD-CDK complexes had no kinase activity. These effects were rescued with reintroduction of p21 and p27, but not reintroduction of cyclin D1 suggesting that CIP/KIP proteins are crucial for cyclin D-CDK activity. In vitro evidence has shown that cyclin D-CDK binding of CIP/KIP is not restricted to p21 and p27 and can also be performed by p57.
124:
stabilization. This sequestering then frees up Cyclin A-, E-CDK2 to hyperphosphorylate Rb and promote progression of the cell cycle. This model is supported by the finding that expression of either wild-type or catalytically inactive CDK4 can sequester CIP/KIP proteins resulting in cyclin E-CDK2 activation. This finding suggests that the ability of cyclinD-CDK complexes to sequester CIP/KIP proteins is predominates their inhibitory activity of CDK2.
97:
The crystal structure of p27 in a complex with cyclinA-CDK2 was published in 1996. The structure shows that p27 interacts with both cyclin A and CDK2. In addition, p27 mimics ATP and inserts itself into the ATP binding site thus preventing ATP binding. This mechanism blocks any kinase activity and
157:
CIP/KIP proteins can regulate transcription indirectly through stabilization of cyclinD-CDK and uninhibiting cyclin-CDK2 complexes that are crucial for Rb phosphorylation and release of the E2F transcription factor. CIP/KIP proteins have also been shown to directly bind transcription factors. For
141:
via a variety of mechanisms. p21 and p27 cleavage are known to promote apoptosis through activation of CDK2 activation. p57 has also been shown to inhibit apoptosis as p57 null mice show a range of developmental defects including cleft palate and a range of intestinal abnormalities associated with
114:
Cyclin D has low affinity for its CDK. Therefore, it was hypothesized that additional proteins were needed to allow for a stable cyclin D-CDK4,6 complex. Growing evidence has shown that CIP/KIP proteins are involved in this stabilization. The first evidence of this came from the observation that
182:
signaling. In addition, fibroblasts deficient for p27 have reduced motility. p27 deficient fibroblasts also have increased levels of stress fibers and focal adhesions. The role of CIP/KIP proteins in motility has also become particularly of interest in cancer where misregulation of p27 could
123:
The divergent role of CIP/KIP proteins based on whether they are bound to CDK2 or CDK4,6 has led to a model whereby CIP/KIP proteins bind to and inactivate CDK2 complexes in early G1; however, following production of Cyclin D, CIP/KIP proteins are removed and repurposed towards cyclin D-CDK
1133:
Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, Shaw P, Yeger H, Morava-Protzner I, Kapusta L, Franssen E, Pritchard KI, Slingerland JM (1997). "Decreased levels of the cell-cycle inhibitor p27Kip1 protein: Prognostic implications in primary breast cancer".
606:
Nagahara H, Vocero-Akbani AM, Snyder EL, Ho A, Latham DG, Lissy NA, Becker-Hapak M, Ezhevsky SA, Dowdy SF (1998). "Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration".
1177:
Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM, Pagano M (1997). "Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas".
84:
and cyclin E-, A-CDK2 complexes. Traditionally it was assumed that CIP/KIP proteins played a role in inhibiting all of these complexes; however it was later discovered that CIP/KIP proteins, while inhibiting
506:
Soos TJ, Kiyokawa H, Yan JS, Rubin MS, Giordano A, DeBlasio A, Bottega S, Wong B, Mendelsohn J, Koff A (1996). "Formation of p27-CDK complexes during the human mitotic cell cycle".
763:
Russo AA, Jeffrey PD, Patten AK, Massague J, Pavletich NP (1996). "Crystal structure of the p27Kip1 cyclin-dependent kinase inhibitor bound to the cyclin A-cdk2 complex".
52:. Their activity primarily involves the binding and inhibition of G1/S- and S-Cdks; however, they have also been shown to play an important role in activating the G1-CDKs
29:
41:
60:. In addition, more recent work has shown that CIP/KIP family members have a number of CDK-independent roles involving regulation of
1517:
914:"Cleavage of p21Cip?Waf1 and P27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade"
1272:"A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice"
1086:"Novel p27(kip1) C-terminal scatter domain mediates Rac-dependent cell migration independent of cell cycle arrest functions"
955:"Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development"
1270:
Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Poyak K, Tsai LH, Broudy V, Perlmutter RM, et al. (1996).
816:"The p21Cip1 and p27Kip1 CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts"
1379:
Besson A, Assoian RK, Roberts JM (2004). "Regulation of the cytoskeleton: an oncogenic function for CDK inhibitors?".
1223:"Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia and pituitary tumors"
996:"p57Kip2 modulates stress-activated signaling by inhibiting c-Jun NH2-terminal kinase/stress-activated protein kinase"
994:
Chang TS, Kim MJ, Ryoo K, Park J, Eom SJ, Shim J, Nakayama KI, Nakayama K, Tomita M, Takahashi K, et al. (2003).
423:"p57kip2, a structureally distinct member of the p21 cip1 cdk inhibitor family, is a candidate tumor suppressor gene"
327:
Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993). "p21 is a universal inhibitor of cyclin kinases".
378:
Toyoshima H, Hunter T (1994). "p27, a novel inhibitor of G1 cyclin/cdk protein kinase activity, is related to p21".
276:
Gu Y, Turek CW, Morgan DO (1993). "Inhibition of CDK 2 activity in vivo by an associated 20K regulatory subunit".
1553:
89:
activity, may also activate cyclin D-CDK4,6 activity by facilitating stable binding between cyclin D and CDK4,6.
86:
57:
53:
706:"Loss of p21 increases sensitivity to ionizing radiation and delays the onset of lymphoma in atm-deficient mice"
464:"Cloning of p57kip2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution"
571:
Coqueret O (2003). "New roles for p21 and p27 cell-cycle inhibitors: A function for each cell compartment?".
61:
49:
25:
99:
145:
CIP/KIP proteins have also been shown to regulate apoptosis via CDK-independent mechanisms. p57 can bind
192:
183:
result in increased proliferation and increased motility which may contribute to more invasive cancers.
1504:
Slingerland J, Pagano MA (2000). "Regulation of the CDK inhibitor p27 and its deregulation in cancer".
44:
These proteins share sequence homology at the N-terminal domain which allows them to bind to both the
1332:
1221:
Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY, Nakayama K (1996).
772:
717:
336:
285:
1558:
530:
LeBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A, Harlow E (1997).
1529:
1465:"Relocalized p27Kip1 tumor suppressor functions as a cytoplasmic metastatic oncogene in melanoma"
1404:
1301:
1252:
1203:
1159:
796:
632:
403:
360:
309:
1035:
Nguyen L, Besson A, Heng J, Schurrmans C, Teboul L, Philpott A, Roberts JM, Guillemot F (2006).
149:, a stress-related kinase, and block its activity, protecting against JNK1-regulated apoptosis.
20:(CDK interacting protein/Kinase inhibitory protein) family is one of two families (CIP/KIP and
1521:
1486:
1445:
1396:
1358:
1293:
1244:
1195:
1151:
1115:
1066:
1037:"P27Kip1 independently promotes neuronal differentiation and migration in the cerebral cortex"
1017:
976:
935:
894:
845:
788:
745:
686:
624:
588:
553:
485:
444:
395:
352:
301:
258:
80:
CIP/KIP family proteins bind a wide range of G1/S and S-phase cyclin-CDK complexes including
1513:
1476:
1435:
1388:
1348:
1340:
1283:
1234:
1187:
1143:
1105:
1097:
1056:
1048:
1007:
966:
925:
884:
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835:
827:
780:
735:
725:
676:
668:
616:
580:
543:
475:
434:
387:
344:
293:
248:
32:) involved in regulating the cell cycle. The CIP/KIP family is made up of three proteins:
421:
Matsuoka S, Edwards M, Bai C, Parker S, Zhang P, Baldini A, Harper JW, Elledge SJ (1995).
1336:
912:
Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM, Ross R (1998).
776:
721:
340:
289:
191:
As cyclin-dependent kinase inhibitors, CIP/KIP proteins have been classically viewed as
1353:
1320:
1061:
1036:
840:
815:
1440:
1423:
1288:
1271:
1239:
1222:
1110:
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913:
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681:
656:
584:
1547:
740:
705:
391:
81:
1408:
1305:
1163:
636:
407:
1533:
1256:
1207:
800:
364:
313:
159:
69:
1481:
1464:
1101:
865:"Requirement of cyclin E-cdk2 inhibition in p16INK4a-mediated growth suppression"
814:
Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ (1999).
831:
730:
657:"p27Kip1 modulates cell migration through the regulation of RhoA activation"
138:
65:
1525:
1490:
1449:
1400:
1119:
1070:
1021:
1012:
995:
849:
690:
592:
262:
253:
236:
1362:
1297:
1248:
1199:
1155:
980:
939:
898:
880:
792:
749:
628:
557:
489:
448:
399:
356:
305:
237:"CDK inhibitors: positive and negative regulators of G1-phase progression"
971:
954:
548:
531:
1518:
10.1002/(SICI)1097-4652(200004)183:1<10::AID-JCP2>3.0.CO;2-I
672:
480:
463:
439:
422:
1191:
1147:
1052:
179:
1321:"The murine gene p27Kip1 is haplo-insufficient for tumour suppression"
1084:
McAllister SS, Becker-Hapak M, Pintucci G, Pagano M, Dowdy SF (2003).
784:
348:
297:
45:
37:
1392:
106:
transcription factor and transcription of cell cycle-related genes.
1344:
175:
146:
620:
532:"New functional activities for the p21 family of CDK inhibitors"
171:
21:
655:
Besson A, Gurian-West M, Schmidt A, Hall A, Roberts JM (2004).
103:
33:
1463:
Denicourt C, Saenz CC, Datnow B, Cui XS, Dowdy SF (2007).
1319:
Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ (1998).
953:
Yan Y, Frisen J, Lee MH, Massague J, Barbacid M (1997).
170:
CIP/KIP proteins have previously been shown to inhibit
162:
promoting differentiation of neural progenitor cells.
158:
example. p27 has been shown to bind to and stabilize
1422:Blain SW, Scher HI, Cordon-Cardo C, Koff A (2003).
1374:
1372:
650:
648:
646:
137:CIP/KIP proteins have been shown to regulate
98:prevents downstream hyper-phosphorylation of
8:
525:
523:
521:
210:
208:
462:Lee MH, Reynisdottir I, Massague J (1995).
230:
228:
226:
501:
499:
1480:
1439:
1424:"p27 as a target for cancer therapeutics"
1352:
1287:
1238:
1109:
1060:
1011:
970:
929:
888:
839:
739:
729:
680:
547:
479:
438:
252:
24:) of mammalian cyclin dependent kinase (
204:
128:Roles outside of cell cycle progression
217:The Cell Cycle: Principles of Control
7:
704:Wang YA, Elson A, Leder P (1997).
14:
508:Cell Growth & Differentiation
863:Jiang H, Chou HS, Zhu L (1998).
119:Model of CIP/KIP G1-S regulation
1000:Journal of Biological Chemistry
1506:Journal of Cellular Physiology
1090:Molecular and Cellular Biology
869:Molecular and Cellular Biology
76:Role in cell cycle progression
1:
1482:10.1158/0008-5472.CAN-07-1375
1441:10.1016/S1535-6108(03)00026-6
1289:10.1016/S0092-8674(00)81239-8
1240:10.1016/S0092-8674(00)81237-4
1102:10.1128/MCB.23.1.216-228.2003
931:10.1016/S1097-2765(00)80055-6
585:10.1016/S0962-8924(02)00043-0
235:Sherr CJ, Roberts JM (1999).
392:10.1016/0092-8674(94)90573-8
102:that allows release of the
1575:
187:Role in cancer and disease
110:cyclinD-CDK4,6 regulation
731:10.1073/pnas.94.26.14590
1041:Genes & Development
959:Genes & Development
832:10.1093/emboj/18.6.1571
661:Genes & Development
536:Genes & Development
468:Genes & Development
427:Genes & Development
241:Genes & Development
93:cyclinA-CDK2 regulation
1013:10.1074/jbc.M309421200
573:Trends in Cell Biology
254:10.1101/gad.13.12.1501
1381:Nature Reviews Cancer
881:10.1128/MCB.18.9.5284
219:. Primers in Biology.
142:increased apoptosis.
972:10.1101/gad.11.8.973
549:10.1101/gad.11.7.847
1337:1998Natur.396..177F
777:1996Natur.382..325R
722:1997PNAS...9414590W
716:(26): 14590–14595.
673:10.1101/gad.1185504
481:10.1101/gad.9.6.639
440:10.1101/gad.9.6.650
341:1993Natur.366..701X
290:1993Natur.366..707G
1192:10.1038/nm0297-231
1148:10.1038/nm0297-227
1053:10.1101/gad.377106
215:Morgan DO (2007).
1475:(19): 9238–9243.
1331:(6707): 177–180.
1047:(11): 1511–1524.
1006:(48): 1158–1164.
771:(6589): 325–331.
615:(12): 1449–1452.
335:(6456): 701–704.
284:(6456): 707–710.
247:(12): 1501–1512.
193:tumor suppressors
1566:
1554:Protein families
1538:
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1501:
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943:
933:
909:
903:
902:
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875:(9): 5284–5290.
860:
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843:
826:(6): 1571–1583.
811:
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804:
785:10.1038/382325a0
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1469:Cancer Research
1462:
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1416:
1393:10.1038/nrc1501
1387:(12): 948–955.
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1370:
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1313:
1269:
1268:
1264:
1220:
1219:
1215:
1180:Nature Medicine
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1136:Nature Medicine
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82:cyclin D-CDK4,6
78:
12:
11:
5:
1572:
1570:
1562:
1561:
1556:
1546:
1545:
1540:
1539:
1496:
1455:
1434:(2): 111–115.
1414:
1368:
1311:
1282:(5): 733–744.
1262:
1233:(5): 701–720.
1213:
1186:(2): 231–234.
1169:
1142:(2): 227–230.
1125:
1096:(1): 216–228.
1076:
1027:
986:
965:(8): 973–983.
945:
924:(4): 553–563.
918:Molecular Cell
904:
855:
806:
755:
696:
667:(8): 851–855.
642:
609:Nature Methods
598:
563:
542:(7): 847–862.
517:
495:
474:(6): 639–649.
454:
433:(6): 650–662.
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28:) inhibitors (
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3:
2:
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153:Transcription
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118:
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92:
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83:
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63:
62:transcription
59:
55:
51:
47:
43:
39:
35:
31:
27:
23:
19:
1512:(1): 10–17.
1509:
1505:
1499:
1472:
1468:
1458:
1431:
1427:
1417:
1384:
1380:
1328:
1324:
1314:
1279:
1275:
1265:
1230:
1226:
1216:
1183:
1179:
1172:
1139:
1135:
1128:
1093:
1089:
1079:
1044:
1040:
1030:
1003:
999:
989:
962:
958:
948:
921:
917:
907:
872:
868:
858:
823:
820:EMBO Journal
819:
809:
768:
764:
758:
713:
709:
699:
664:
660:
621:10.1038/4042
612:
608:
601:
579:(2): 65–70.
576:
572:
566:
539:
535:
511:
507:
471:
467:
457:
430:
426:
416:
386:(1): 67–74.
383:
379:
373:
332:
328:
322:
281:
277:
271:
244:
240:
216:
190:
169:
166:Cytoskeleton
160:Neurogenin-2
156:
144:
136:
122:
113:
96:
79:
70:cytoskeleton
17:
15:
1428:Cancer Cell
1559:Cell cycle
1548:Categories
514:: 135–146.
199:References
68:, and the
147:JNK1/SAPK
139:apoptosis
133:Apoptosis
66:apoptosis
1526:10699961
1491:17909030
1450:12620406
1409:12663308
1401:15573116
1306:15490866
1164:25460889
1120:12482975
1071:16705040
1022:12963725
850:10075928
691:15078817
637:10962704
593:12559756
408:39776582
263:10385618
1534:8756686
1363:9823898
1354:5395202
1333:Bibcode
1298:8646781
1257:2009281
1249:8646779
1208:3164478
1200:9018245
1156:9018244
1062:1475763
981:9136926
940:9660939
899:9710613
841:1171245
801:4284942
793:8684460
773:Bibcode
750:9405657
718:Bibcode
629:9846587
558:9106657
490:7729683
449:7729684
400:8033213
365:4362507
357:8259214
337:Bibcode
314:4368793
306:8259216
286:Bibcode
180:Cofilin
18:CIP/KIP
1532:
1524:
1489:
1448:
1407:
1399:
1361:
1351:
1325:Nature
1304:
1296:
1255:
1247:
1206:
1198:
1162:
1154:
1118:
1111:140659
1108:
1069:
1059:
1020:
979:
938:
897:
890:109114
887:
848:
838:
799:
791:
765:Nature
748:
738:
689:
682:395846
679:
635:
627:
591:
556:
488:
447:
406:
398:
363:
355:
329:Nature
312:
304:
278:Nature
261:
178:/LIMK/
46:cyclin
1530:S2CID
1405:S2CID
1302:S2CID
1253:S2CID
1204:S2CID
1160:S2CID
797:S2CID
741:25064
633:S2CID
404:S2CID
361:S2CID
310:S2CID
1522:PMID
1487:PMID
1446:PMID
1397:PMID
1359:PMID
1294:PMID
1276:Cell
1245:PMID
1227:Cell
1196:PMID
1152:PMID
1116:PMID
1067:PMID
1018:PMID
977:PMID
936:PMID
895:PMID
846:PMID
789:PMID
746:PMID
710:PNAS
687:PMID
625:PMID
589:PMID
554:PMID
486:PMID
445:PMID
396:PMID
380:Cell
353:PMID
302:PMID
259:PMID
176:ROCK
87:CDK2
58:CDK6
56:and
54:CDK4
48:and
30:CKIs
22:INK4
16:The
1514:doi
1510:183
1477:doi
1436:doi
1389:doi
1349:PMC
1341:doi
1329:396
1284:doi
1235:doi
1188:doi
1144:doi
1106:PMC
1098:doi
1057:PMC
1049:doi
1008:doi
1004:278
967:doi
926:doi
885:PMC
877:doi
836:PMC
828:doi
781:doi
769:382
736:PMC
726:doi
677:PMC
669:doi
617:doi
581:doi
544:doi
476:doi
435:doi
388:doi
345:doi
333:366
294:doi
282:366
249:doi
172:Rho
104:E2F
50:CDK
42:p57
40:,
38:P27
34:p21
26:CDK
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