Open Access

Speeding through cell cycle roadblocks: Nuclear cyclin D1-dependent kinase and neoplastic transformation

Cell Division20083:12

https://doi.org/10.1186/1747-1028-3-12

Received: 14 August 2008

Accepted: 02 September 2008

Published: 02 September 2008

Abstract

Mitogenic induction of cyclin D1, the allosteric regulator of CDK4/6, is a key regulatory event contributing to G1 phase progression. Following the G1/S transition, cyclin D1 activation is antagonized by GSK3β-dependent threonine-286 (Thr-286) phosphorylation, triggering nuclear export and subsequent cytoplasmic degradation mediated by the SCFFbx4-αBcrystallin E3 ubiquitin ligase. Although cyclin D1 overexpression occurs in numerous malignancies, overexpression of cyclin D1 alone is insufficient to drive transformation. In contrast, cyclin D1 mutants refractory to phosphorylation-dependent nuclear export and degradation are acutely transforming. This raises the question of whether overexpression of cyclin D1 is a significant contributor to tumorigenesis or an effect of neoplastic transformation. Significantly, recent work strongly supports a model wherein nuclear accumulation of cyclin D1-dependent kinase during S-phase is a critical event with regard to transformation. The identification of mutations within SCFFbx4-αBcrystallin ligase in primary tumors provides mechanistic insight into cyclin D1 accumulation in human cancer. Furthermore, analysis of mouse models expressing cyclin D1 mutants refractory to degradation indicate that nuclear cyclin D1/CDK4 kinase triggers DNA re-replication and genomic instability. Collectively, these new findings provide a mechanism whereby aberrations in post-translational regulation of cyclin D1 establish a cellular environment conducive to mutations that favor neoplastic growth.

Introduction

Mitogenic signalling induces transcription and translation of the D-type cyclins, the allosteric regulators of CDK4/6, during G1 phase coupling growth stimuli to cell cycle progression [1]. Active cyclin D1/CDK4 complexes translocate to the nucleus and phosphorylate the retinoblastoma protein (Rb) and related pocket proteins, thereby triggering E2F-dependent transcription of genes required for S-phase entry [26]. The timely expression and accumulation of cyclin D1 is ensured through several mechanisms. Initially, cyclin D1 expression requires activation of the Raf-Mek-Erk kinase cascade [710]. This increased expression is accompanied by phosphatidylinositol 3-kinase and Akt-dependent increases in cyclin D1 translation and decreased cyclin D1 protein degradation [1113]. Following the G1/S transition, cyclin D1 is rapidly phosphorylated by GSK3β on Thr-286, triggering CRM1-dependent nuclear export [13]. Thr-286 phosphorylated cyclin D1 is recognized by Fbx4 and the co-factor αB crystallin and is subsequently poly-ubiquitylated and degraded by the 26S proteasome [14].

While cyclin D1 overexpression occurs frequently in human cancer and is considered a causative factor in many tumor types, simple over-expression of wild type cyclin D1 is insufficient to drive neoplastic transformation [15]. In contrast, cyclin D1 mutants refractory to phosphorylation and subsequent cytoplasmic proteasomal degradation are acutely transforming in vitro and in vivo [15, 16] implying that compartmentalization of cyclin D1 complexes is essential for cell homeostasis. Indeed, mutations that directly impact on cyclin D1 nuclear export and subsequent proteolysis have been identified in human tumors [17, 18]. However, the occurrence of such mutations is rare compared to the frequency of cyclin D1 overexpression. Implicit to this data, if cyclin D1 is a driver oncogene, its overexpression in many cancers must be secondary to tumor-specific alterations that modify its subcellular location during the cell cycle. Here, we discuss recent work to address these questions.

Cancer-derived cyclin D1 mutations

Cyclin D1 overexpression occurs in carcinomas of the breast, esophagus, head and neck, and lung; in a majority of these cases, alterations in gene expression cannot account for its overexpression. Perturbations in cyclin D1 degradation have been suggested as the primary contributor in a large percentage of cases. Indeed mutations that interfere with Thr-286 phosphorylation occur, but are rare. Such mutations have been noted in endometrial and esophageal cancer [17, 18]. For example, of single-base substitutions in the CCND1 gene changing proline-287 (Pro-287) to a serine or threonine residue in endometrioid endometrial carcinoma correlates with overexpression of cyclin D1 in the nucleus of neoplastic cells. Additionally, a 12-base pair in frame deletion corresponding to deletion of amino acids 289–292 was reported with overexpression of cyclin D1 [17]. Significantly, subsequent analyses revealed that disruption of Pro-287 abrogates GSK3β-dependent phosphorylation of Thr-286, resulting in nuclear localization of cyclin D1, and deletion of residues 289–292 impairs cyclin D1 binding to CRM1, also resulting in nuclear accumulation [18, 19].

In accordance with endometrial cancer studies, recently identified cyclin D1 mutations in esophageal cancer and tumor-derived cell lines also disrupt Thr-286 phosphorylation [18]. Sequencing of cyclin D1 (CCND1) in a panel of 90 patient esophageal carcinomas revealed mutation of Thr-286 to arginine and a deletion of C-terminal residues 266–295. Additionally, screening of human tumor-derived esophageal carcinoma cell lines also identified a Pro-287 to alanine mutation in three of these lines [18].

Alternative splicing may also contribute to cancer specific accumulation of cyclin D1 proteins that cannot undergo cytoplasmic degradation [20]. Tumor-specific alternative splicing produces a truncated transcript lacking exon 5, the region encoding the C-terminal Thr-286; this cyclin D1 transcript b (D1b) produces a constitutively nuclear protein refractory to proteasomal degradation [21]. Current work suggests that D1b may be expressed in up to 40% of primary esophageal carcinomas [21]. While cyclin D1b stability is only moderately increased relative to wild type protein, it is refractory to nuclear export and therefore exhibits constitutively nuclear localization. As might be anticipated, expression of cyclin D1b promotes neoplastic transformation in vitro, much like the phosphorylation-deficient T286A mutant [15, 21]. It is currently unclear what determines alterations in cyclin D1 splicing; polymorphisms that occur in the splice-donor site at the exon 4/intron boundary have been implicated. However, cyclin D1b has been detected in cells that do not exhibit polymorphic residues implicating the occurrence of alternative mechanisms [21].

Disruption of SCFFbx4-αBcrystallin function: novel insights into cyclin D1 overexpression

Cell cycle progression is driven by alternating phases of cyclin expression and destruction. Degradation is coordinated by substrate ubiquitylation and destruction via the 26S proteasome [22, 23]. Poly-ubiquitylation of substrate proteins is catalyzed by the sequential activity of a ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3) [24]. The Skp1-Cul1-F box (SCF) E3 ubiquitin ligases facilitate polyubiquitylation of phosphorylated substrates; among the substrates are many of the key regulators of G1 progression [25]. We recently identified the E3 ubiquitin ligase that directs phosphorylation-dependent polyubiquitylation of cyclin D1, SCFFbx4-αB crystallin [14]. Substrate recognition by this ligase is analogous with Skp2/Cks1 in that it is directed by the F box protein Fbx4 in concert with a cofactor, αB crystallin [14].

Given the low frequency of mutations within cyclin D1 that directly impact is turnover, a logical prediction was the occurrence of inactivating mutations in its E3 ligase. The first clue to cyclin D1 ligase involvement came from analysis of several breast cancer cell lines exhibiting increased cyclin D1 half-life without mutations disrupting phosphorylation. These analyses revealed that MCF-7 and MDA-MB-231 cells lack αB crystallin expression as a consequence of chromosome deletions. In addition, tumor microarray analysis of esophageal carcinomas revealed a reduction in both αB crystallin and Fbx4 mRNA levels in tumor tissues [14]. Collectively, these findings implicated the cyclin D1 ligase as a target in tumorigenesis, with proteins such as αB crystallin or Fbx4 functioning as putative tumor suppressors.

Significantly, recent assessment of the Fbx4 sequence in primary esophageal carcinoma samples identified hemizygous, missense mutations in 14 percent of the tumors; no mutations occurred in αB crystallin or CCND1 genes in tumors expressing mutated Fbx4. A high percentage of mutations reside within a putative Fbx4 dimerization domain, while others target Ser-12 in the N-terminus. Additionally, one mutation identified within the F box domain results in production of a dominant negative protein incapable of recruiting Skp1 and Cul1[26]. The residues targeted in cancer suggest a model wherein Fbx4 is phosphorylated on Ser-12 and functions as a dimer. While substrate phosphorylation serves as a critical step in regulating SCF ligase function, several studies indicated that F box proteins such as Fbw7 and β-TrCP can form dimers, potentially regulating ligase activity [2730].

Further analysis of the cyclin D1 ligase revealed that GSK3β, the kinase responsible for cyclin D1 Thr-286 phosphorylation, also catalyzes phosphorylation of Fbx4 Ser-12. Fbx4 phosphorylation correlates with low cyclin D1 expression during G2/M and early G1, with a marked decrease during cell cycle entry due to growth factor-dependent GSK3β inhibition [11]. Fbx4 phosphorylation increases again at the G1/S boundary as GSK3β becomes active and temporally controls ligase activation and cyclin D1 phosphorylation. These findings raise the question of how Fbx4 phosphorylation regulates ligase function. Additional work demonstrated that Fbx4 forms homodimers in a phosphorylation- and cell cycle-dependent manner [26]. Fbx4 homodimerization is dependent on Ser-12 phosphorylation; disruption of this residue impairs the ubiquitylation activity of this ligase [26].

The tumorigenic potential of Fbx4 mutations disrupting phosphorylation and dimerization was assessed in vitro, revealing that such mutations are indeed transforming [26]. These findings suggest that mutation of Ser-12 or residues within the Fbx4 dimerization domain impairs ligase function, contributing to cyclin D1 accumulation. Studies over the past several years have identified mutations in both cyclin D1 and its E3 ubiquitin ligase that impair proteasomal degradation and promote nuclear accumulation of cyclin D1/CDK4 complexes (summarized in Table 1). Therefore, delineating the mechanism underlying nuclear cyclin D1-driven transformation is critical for understanding the role of cyclin D1 in tumorigenesis and development of therapeutic strategies for treatment of cancers overexpressing this protein.
Table 1

Summary of mutations targeting cyclin D1 phosphorylation or ligase function

Target

Mutation

Consequence

Tumor Type

Reference

Cyclin D1

T286R

Constitutively Nuclear

Esophageal

[18]

Cyclin D1

Δ266–295

Constitutively Nuclear

Esophageal

[18]

Cyclin D1

P287A

Constitutively Nuclear

Tumor-derived esophageal carcinoma cell lines TE3, TE7, and TE12

[18]

Cyclin D1

P287S/T

Constitutively Nuclear

Endometrial

[17]

Cyclin D1

Δ289–292

Constitutively Nuclear

Endometrial

[17]

αB crystallin

Chromosome 11 deletion

Impaired ligase activity

Tumor-derived breast cancer cell lines (MCF-7, MDA-MB 231)

[14]

Fbx4

S8R

Impaired ligase activity

Esophageal

[26]

Fbx4

S12L

Disrupts phosphorylation

Esophageal

[26]

Fbx4

P13S

Disrupts phosphorylation

Esophageal

[26]

Fbx4

L23Q

Dimerization-deficient

Esophageal

[26]

Fbx4

P76T

Impaired Skp1 binding

Esophageal

[26]

Mutations disrupting GSK3β-dependent cyclin D1 phosphorylation and nuclear export include mutation of Thr-286, Pro-287, and deletion of residues corresponding to the CRM1 binding site. Mutations targeting the SCFFbx4-αB crystallin E3 ubiquitin ligase result in impaired ligase activity and subsequent cyclin D1/CDK4 accumulation in the nucleus.

Inhibition of cyclin D1 degradation promotes genomic instability

Aberrant nuclear accumulation of cyclin D1 during S-phase drives cell transformation in vitro and B-cell lymphomagenesis in mice [15, 16]. Recent evidence links nuclear retention of active cyclin D1/CDK4 complexes with genomic instability, providing a novel mechanism wherein cyclin D1 stabilization initiates tumor formation. Nuclear accumulation of active cyclin D1-dependent kinase was found to interfere with Cdt1 proteolysis [31]. Cdt1 is a component of the pre-replicative complex that promotes loading of the replicative helicase during late G1 phase [32, 33]. The failure to degrade Cdt1 during S-phase has been shown to contribute to DNA re-replication in several systems [34, 35]. In cells harbouring nuclear cyclin D1, Cdt1 proteolysis was disrupted due to repression of Cul4A and Cul4B expression. Cul4 proteins serve as scaffolds for the E3 ligase that regulates Cdt1 [36, 37]. Ultimately, nuclear cyclin D1/CDK4 complexes facilitate stabilization of Cdt1 during S-phase, with concurrent maintenance of the MCM helicase on chromatin, resulting in DNA re-replication and activation of DNA damage checkpoint signalling [31].

Active cyclin D1/CDK4 complexes influence transcriptional regulation of the Cul4 proteins; however, the precise mechanism of regulation remains to be elucidated. Strikingly, impaired cyclin D1 ligase function results in nuclear accumulation of active cyclin D1/CDK4 complexes, accumulation of Cdt1, and triggers cellular transformation analogous to cyclin D1 T286A [26]. Taken together, data elucidating the role of nuclear cyclin D1 in neoplastic transformation support a model wherein disruption of cyclin D1 phosphorylation or SCFFbx4-αBcrystallin activation generate genomic instability, ultimately driving tumor formation (Figure 1).
Figure 1

Cyclin D1 Regulatory Pathways are Targeted in Human Cancer. Cyclin D1 protein accumulation is tightly controlled via phosphorylation-dependent proteolysis. Mutations targeting cyclin D1 phosphorylation or degradation contribute to neoplastic transformation. Specific disruption of Thr-286 phosphorylation occurs in endometrial and esophageal carcinoma, while mutations preventing Crm1 binding occur in endometrial cancer. Mutations targeting Fbx4 have been identified in esophageal cancer, and αB crystallin loss occurs in tumor-derived breast carcioma cell lines. Disruption of cyclin D1 proteolysis promotes accumulation of active cyclin D1/CDK4 kinase, triggering DNA re-replication and subsequent genomic instability necessary to drive neoplastic transformation.

Genomic integrity is monitored by cell cycle checkpoints that promote cell cycle arrest or apoptosis upon detection of damaged DNA [38]. Chronic activation of checkpoints may provide selective pressure for deletion or mutation of critical tumor suppressors such as p53 [39, 40]. Consistent with this notion, cyclin D1T286A-dependent tumorigenesis is accompanied by activation of the DNA damage checkpoint pathway and loss of p53 [31]. The deleterious effects of nuclear cyclin D1/CDK4 complexes could then have two different effects on cellular transformation. Chronic checkpoint activation can induce selective pressure for loss of tumor suppressors, thereby providing such cells not only with a growth advantage but also the propensity for additional genomic instability.

Cyclin D1 protein accumulation in tumors: potential therapeutic strategies

Provided with this new data suggesting that cyclin D1-dependent kinase contributes to neoplasia at least in part through perturbations in DNA replication and loss of genomic integrity, can we utilize this information for increased therapeutic modalities? One scenario might be to take advantage of the fact that tumors harbouring mutations in cyclin D1 or Fbx4 have a compromised DNA damage checkpoint due to loss of p53. In theory, treatment of normal cells with chemotherapeutic agents that generate DNA crosslinks should trigger an intra S-phase checkpoint, thereby providing an opportunity for repair. Expression of stabilized cyclin D1 should promote maintenance of Cdt1 and MCM complexes and in so doing promote continued origin firing without allowing for repair of damaged DNA, ultimately resulting in mitotic catastrophe. Further work is required to investigate how alterations in cyclin D1 proteolysis might influence cellular responses to DNA damaging therapeutics.

The alternative is the development of drugs that directly target the kinase subunits that cyclin D1 regulates. If continued activation of CDK4/6 is required for tumor proliferation and survival, such drugs may have significant clinical use. Consistent with this notion of oncogene addiction, treatment of mammary epithelial cells derived from murine tumors harbouring a MMTV-T286A transgene with the CDK4/6 inhibitor PD0332991 [41] triggered G1 arrest [42]. Therefore, CDK4/6 activity is a potential target to prevent cyclin D1-driven proliferation.

Concluding Remarks

Phosphorylation-dependent nuclear export and subsequent degradation of cyclin D1 is essential to maintain cellular homeostasis. Disruption of this regulatory pathway has been extensively shown to promote neoplastic transformation; however, the precise mechanism of this event has been elusive. Significantly, recent work revealed that nuclear accumulation of active cyclin D1/CDK4 complexes generates genomic instability through a mechanism of Cdt1 stabilization and DNA re-replication. Furthermore, mutations targeting SCFFbx4-αB crystallin in human cancers implicate ligase function in cyclin D1 overexpression and subsequent nuclear accumulation of active cyclin D1/CDK4 complexes. Importantly, GSK3β functions as the master switch, turning on cyclin D1 destruction at the G1/S transition by regulating both ligase activation and cyclin D1 phosphorylation. Given the phenotypic outcome of accumulated nuclear cyclin D1/CDK4 complexes, further mechanistic investigation is required for development of novel therapeutic strategies to promote tumor cell death in cancers overexpressing cyclin D1.

Declarations

Acknowledgements

This work was supported by CA93237 (NIH); JAD is a Leukemia & Lymphoma Society Scholar.

Authors’ Affiliations

(1)
The Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania

References

  1. Sherr CJ: Mammalian G1 cyclins. Cell 1993,73(6):1059–1065. 10.1016/0092-8674(93)90636-5View ArticlePubMedGoogle Scholar
  2. Hatakeyama M, Brill JA, Fink GR, Weinberg RA: Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. Genes Dev 1994,8(15):1759–1771. 10.1101/gad.8.15.1759View ArticlePubMedGoogle Scholar
  3. Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC: Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 1999,98(6):859–869. 10.1016/S0092-8674(00)81519-6View ArticlePubMedGoogle Scholar
  4. Calbo J, Parreno M, Sotillo E, Yong T, Mazo A, Garriga J, Grana X: G1 cyclin/cyclin-dependent kinase-coordinated phosphorylation of endogenous pocket proteins differentially regulates their interactions with E2F4 and E2F1 and gene expression. J Biol Chem 2002,277(52):50263–50274. 10.1074/jbc.M209181200View ArticlePubMedGoogle Scholar
  5. Leng X, Noble M, Adams PD, Qin J, Harper JW: Reversal of growth suppression by p107 via direct phosphorylation by cyclin D1/cyclin-dependent kinase 4. Mol Cell Biol 2002,22(7):2242–2254. 10.1128/MCB.22.7.2242-2254.2002View ArticlePubMedPubMed CentralGoogle Scholar
  6. Sherr CJ: Cancer cell cycles. Science 1996,274(5293):1672–1677. 10.1126/science.274.5293.1672View ArticlePubMedGoogle Scholar
  7. Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, Pestell RG: Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J Biol Chem 1995,270(40):23589–23597. 10.1074/jbc.270.40.23589View ArticlePubMedGoogle Scholar
  8. Winston JT, Coats SR, Wang YZ, Pledger WJ: Regulation of the cell cycle machinery by oncogenic ras. Oncogene 1996,12(1):127–134.PubMedGoogle Scholar
  9. Aktas H, Cai H, Cooper GM: Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1. Mol Cell Biol 1997,17(7):3850–3857.PubMedPubMed CentralView ArticleGoogle Scholar
  10. Cheng M, Sexl V, Sherr CJ, Roussel MF: Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1). Proc Natl Acad Sci U S A 1998,95(3):1091–1096. 10.1073/pnas.95.3.1091View ArticlePubMedPubMed CentralGoogle Scholar
  11. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA: Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995,378(6559):785–789. 10.1038/378785a0View ArticlePubMedGoogle Scholar
  12. Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD: Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 1997,22(7):267–272. 10.1016/S0968-0004(97)01061-XView ArticlePubMedGoogle Scholar
  13. Diehl JA, Cheng M, Roussel MF, Sherr CJ: Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998,12(22):3499–3511. 10.1101/gad.12.22.3499View ArticlePubMedPubMed CentralGoogle Scholar
  14. Lin DI, Barbash O, Kumar KG, Weber JD, Harper JW, Klein-Szanto AJ, Rustgi A, Fuchs SY, Diehl JA: Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF(FBX4-alphaB crystallin) complex. Mol Cell 2006,24(3):355–366. 10.1016/j.molcel.2006.09.007View ArticlePubMedPubMed CentralGoogle Scholar
  15. Alt JR, Cleveland JL, Hannink M, Diehl JA: Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev 2000,14(24):3102–3114. 10.1101/gad.854900View ArticlePubMedPubMed CentralGoogle Scholar
  16. Gladden AB WR Aggarwal P, Wasik MA, Diehl JA: Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma . Oncogene 2006, 25: 998–1007. 10.1038/sj.onc.1209147View ArticlePubMedPubMed CentralGoogle Scholar
  17. Moreno-Bueno G, Rodriguez-Perales S, Sanchez-Estevez C, Hardisson D, Sarrio D, Prat J, Cigudosa JC, Matias-Guiu X, Palacios J: Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene 2003,22(38):6115–6118. 10.1038/sj.onc.1206868View ArticlePubMedGoogle Scholar
  18. Benzeno S, Lu F, Guo M, Barbash O, Zhang F, Herman JG, Klein PS, Rustgi A, Diehl JA: Identification of mutations that disrupt phosphorylation-dependent nuclear export of cyclin D1. Oncogene 2006,25(47):6291–6303. 10.1038/sj.onc.1209644View ArticlePubMedGoogle Scholar
  19. Benzeno S, Diehl JA: C-terminal sequences direct cyclin D1-CRM1 binding. J Biol Chem 2004,279(53):56061–56066. 10.1074/jbc.M411910200View ArticlePubMedGoogle Scholar
  20. Betticher DC, Thatcher N, Altermatt HJ, Hoban P, Ryder WD, Heighway J: Alternate splicing produces a novel cyclin D1 transcript. Oncogene 1995,11(5):1005–1011.PubMedGoogle Scholar
  21. Lu F, Gladden AB, Diehl JA: An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene. Cancer Res 2003,63(21):7056–7061.PubMedGoogle Scholar
  22. Evans T, Rosenthal ET, Youngblom J, Distel D, Hunt T: Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 1983,33(2):389–396. 10.1016/0092-8674(83)90420-8View ArticlePubMedGoogle Scholar
  23. Glotzer M, Murray AW, Kirschner MW: Cyclin is degraded by the ubiquitin pathway. Nature 1991,349(6305):132–138. 10.1038/349132a0View ArticlePubMedGoogle Scholar
  24. Ciechanover A: The ubiquitin-proteasome proteolytic pathway. Cell 1994,79(1):13–21. 10.1016/0092-8674(94)90396-4View ArticlePubMedGoogle Scholar
  25. Skowyra D, Craig KL, Tyers M, Elledge SJ, Harper JW: F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell 1997,91(2):209–219. 10.1016/S0092-8674(00)80403-1View ArticlePubMedGoogle Scholar
  26. Barbash O, Zamfirova P, Lin DI, Chen X, Yang K, Nakagawa H, Lu F, Rustgi AK, Diehl JA: Mutations in Fbx4 Inhibit Dimerization of the SCF(Fbx4) Ligase and Contribute to Cyclin D1 Overexpression in Human Cancer. Cancer Cell 2008,14(1):68–78. 10.1016/j.ccr.2008.05.017View ArticlePubMedPubMed CentralGoogle Scholar
  27. Tang X, Orlicky S, Lin Z, Willems A, Neculai D, Ceccarelli D, Mercurio F, Shilton BH, Sicheri F, Tyers M: Suprafacial orientation of the SCFCdc4 dimer accommodates multiple geometries for substrate ubiquitination. Cell 2007,129(6):1165–1176. 10.1016/j.cell.2007.04.042View ArticlePubMedGoogle Scholar
  28. Welcker M, Clurman BE: Fbw7/hCDC4 dimerization regulates its substrate interactions. Cell Div 2007, 2: 7. 10.1186/1747-1028-2-7View ArticlePubMedPubMed CentralGoogle Scholar
  29. Zhang W, Koepp DM: Fbw7 isoform interaction contributes to cyclin E proteolysis. Mol Cancer Res 2006,4(12):935–943. 10.1158/1541-7786.MCR-06-0253View ArticlePubMedGoogle Scholar
  30. Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M, Furuichi K, Shikama H, Tanaka K: Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination. J Biol Chem 2000,275(4):2877–2884. 10.1074/jbc.275.4.2877View ArticlePubMedGoogle Scholar
  31. Aggarwal P, Lessie MD, Lin DI, Pontano L, Gladden AB, Nuskey B, Goradia A, Wasik MA, Klein-Szanto AJ, Rustgi AK, Bassing CH, Diehl JA: Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication. Genes Dev 2007,21(22):2908–2922. 10.1101/gad.1586007View ArticlePubMedPubMed CentralGoogle Scholar
  32. Maiorano D, Moreau J, Mechali M: XCDT1 is required for the assembly of pre-replicative complexes in Xenopus laevis. Nature 2000,404(6778):622–625. 10.1038/35007104View ArticlePubMedGoogle Scholar
  33. Nishitani H, Lygerou Z, Nishimoto T, Nurse P: The Cdt1 protein is required to license DNA for replication in fission yeast. Nature 2000,404(6778):625–628. 10.1038/35007110View ArticlePubMedGoogle Scholar
  34. Li A, Blow JJ: Cdt1 downregulation by proteolysis and geminin inhibition prevents DNA re-replication in Xenopus. Embo J 2005,24(2):395–404. 10.1038/sj.emboj.7600520View ArticlePubMedPubMed CentralGoogle Scholar
  35. Vaziri C, Saxena S, Jeon Y, Lee C, Murata K, Machida Y, Wagle N, Hwang DS, Dutta A: A p53-dependent checkpoint pathway prevents rereplication. Mol Cell 2003,11(4):997–1008. 10.1016/S1097-2765(03)00099-6View ArticlePubMedGoogle Scholar
  36. Nishitani H, Sugimoto N, Roukos V, Nakanishi Y, Saijo M, Obuse C, Tsurimoto T, Nakayama KI, Nakayama K, Fujita M, Lygerou Z, Nishimoto T: Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis. Embo J 2006,25(5):1126–1136. 10.1038/sj.emboj.7601002View ArticlePubMedPubMed CentralGoogle Scholar
  37. Zhong W, Feng H, Santiago FE, Kipreos ET: CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing. Nature 2003,423(6942):885–889. 10.1038/nature01747View ArticlePubMedGoogle Scholar
  38. Kastan MB, Bartek J: Cell-cycle checkpoints and cancer. Nature 2004,432(7015):316–323. 10.1038/nature03097View ArticlePubMedGoogle Scholar
  39. Bartkova J Horejsí Z, Koed K, Kramer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland JM, Lukas C, Orntoft T, Lukas J, Bartek J: DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis . Nature 2005,434(7035):864–870. 10.1038/nature03482View ArticlePubMedGoogle Scholar
  40. Gorgoulis VG Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, Venere M, Ditullio RA Jr, Kastrinakas NG, Levy B, Kletsas D, Yoneta A, Herlyn M, Kittas C, Halazonetis TD: Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions . Nature 2005,434(7035):907–913. 10.1038/nature03485View ArticlePubMedGoogle Scholar
  41. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL: Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004,3(11):1427–1438.PubMedGoogle Scholar
  42. Lin DI, Lessie MD, Gladden AB, Bassing CH, Wagner KU, Diehl JA: Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis. Oncogene 2007, 27: 1231–42. 10.1038/sj.onc.1210738View ArticlePubMedPubMed CentralGoogle Scholar

Copyright

© Pontano and Diehl; licensee BioMed Central Ltd. 2008

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement