Cks1: Structure, Emerging Roles and Implications in Multiple Cancers


Deregulation of the cell cycle results in loss of normal control mechanisms that prevent aberrant cell proliferation and cancer progression. Regulation of the cell cycle is a highly complex process with many layers of control. One of these mechanisms involves timely degradation of CDK inhibitors (CKIs) like p27Kip1 by the ubiquitin proteasomal system (UPS). Cks1 is a 9 kDa protein which is frequently overexpressed in different tumor subtypes, and has pleiotropic roles in cell cycle progression, many of which remain to be fully characterized. One well characterized molecular role of Cks1 is that of an essential adaptor that regulates p27Kip1 abundance by facilitating its interaction with the SCF-Skp2 E3 ligase which appends ubiquitin to p27Kip1 and targets it for degradation through the UPS. In addition, emerging research has uncovered p27Kip1-independent roles of Cks1 which have provided crucial insights into how it may be involved in cancer progression. We review here the structural features of Cks1 and their functional implications, and also some recently identified Cks1 roles and their involvement in breast and other cancers.

Share and Cite:

V. Khattar and J. Thottassery, "Cks1: Structure, Emerging Roles and Implications in Multiple Cancers," Journal of Cancer Therapy, Vol. 4 No. 8, 2013, pp. 1341-1354. doi: 10.4236/jct.2013.48159.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] L. Yamasaki and M. Pagano, “Cell Cycle, Proteolysis and Cancer,” Current Opinion in Cell Biology, Vol. 16, No. 6, 2004, pp. 623-628.
[2] K. Vermeulen, D. R. Van Bockstaele and Z. N. Berneman, “The Cell Cycle: A Review of Regulation, Deregulation and Therapeutic Targets in Cancer,” Cell Proliferation, Vol. 36, No. 3, 2003, pp. 131-149.
[3] M. Malumbres and M. Barbacid, “Cell Cycle, CDKs and Cancer: A Changing Paradigm,” Nature Reviews Cancer, Vol. 9, No. 3, 2009, pp. 153-166.
[4] C. J. Sherr and J. M. Roberts, “CDK Inhibitors: Positive and Negative Regulators of G1-Phase Progression,” Genes & Development, Vol. 13, No. 12, 1999, pp. 1501-1512. 10.1101/gad.13.12.1501
[5] Z. Lu and T. Hunter, “Ubiquitylation and Proteasomal Degradation of the p21(Cip1), p27(Kip1) and p57(Kip2) CDK Inhibitors,” Cell Cycle, Vol. 9, No. 12, 2010, pp. 2342-2352. cc.9.12.11988
[6] S. I. Reed, “The Ubiquitin-Proteasome Pathway in Cell Cycle Control,” Results and Problems in Cell Differentiation, Vol. 42, 2006, pp. 147-181.
[7] A. Hershko and A. Ciechanover, “The Ubiquitin System,” Annual Review of Biochemistry, Vol. 67, 1998, pp. 425-479.
[8] K. I. Nakayama, S. Hatakeyama and K. Nakayama, “Regulation of the Cell Cycle at the G1-S Transition by Proteolysis of Cyclin E and p27Kip1,” Biochemical and Biophysical Research Communications, Vol. 282, No. 4, 2001, pp. 853-860.
[9] S. Kotoshiba and K. Nakayama, “The Degradation of p27 and Cancer,” Nihon Rinsho, Vol. 63, No. 11, 2005, pp. 2047-2056.
[10] R. J. Sheaff, et al., “Cyclin E-CDK2 Is a Regulator of p27Kip1,” Genes & Development, Vol. 11, No. 11, 1997, pp. 1464-1478.
[11] A. C. Carrano, et al., “SKP2 Is Required for Ubiquitin-Mediated Degradation of the CDK Inhibitor p27,” Nature Cell Biology, Vol. 1, No. 4, 1999, pp. 193-199.
[12] D. Ganoth, et al., “The Cell-Cycle Regulatory Protein Cks1 Is Required for SCF(Skp2)-Mediated Ubiquitinylation of p27,” Nature Cell Biology, Vol. 3, No. 3, 2001, pp. 321-324. 10.1038/35060126
[13] C. Spruck, et al., “A CDK-Independent Function of Mammalian Cks1: Targeting of SCF(Skp2) to the CDK Inhibitor p27Kip1,” Molecular Cell, Vol. 7, No. 3, 2001, pp. 639-650. S1097-2765(01)00210-6
[14] C. A. Auld, C. D. Caccia and R. F. Morrison, “Hormonal Induction of Adipogenesis Induces Skp2 Expression through PI3K and MAPK Pathways,” Journal of Cellular Biochemistry, Vol. 100, No. 1, 2007, pp. 204-216.
[15] K. V. Bhatt, et al., “Mutant B-RAF Signaling and Cyclin D1 Regulate Cks1/S-Phase Kinase-Associated Protein 2-Mediated Degradation of p27Kip1 in Human Melanoma Cells,” Oncogene, Vol. 26, No. 7, 2007, pp. 1056-1066.
[16] D. F. Calvisi, et al., “Dual-Specificity Phosphatase 1 Ubiquitination in Extracellular Signal-Regulated KinaseMediated Control of Growth in Human Hepatocellular Carcinoma,” Cancer Research, Vol. 68, No. 11, 2008, pp. 4192-4200.
[17] C. J. Dal, et al., “Distinct Functional Significance of Akt and mTOR Constitutive Activation in Mantle Cell Lymphoma,” Blood, Vol. 111, No. 10, 2008, pp. 5142-5151.
[18] R. Hu and A. E. Aplin, “AlphaB-Crystallin Is Mutant BRAF Regulated and Contributes to Cyclin D1 Turnover in Melanocytic Cells,” Pigment Cell & Melanoma Research, Vol. 23, No. 2, 2010, pp. 201-209.
[19] E. K. Lee, et al., “Cell-Cycle Regulator Cks1 Promotes Hepatocellular Carcinoma by Supporting NF-kappaB-Dependent Expression of Interleukin-8,” Cancer Research, Vol. 71, No. 21, 2011, pp. 6827-6835.
[20] S. W. Lee, et al., “Akt and Cks1 Are Related with Lymph Node Metastasis in Gastric Adenocarcinoma,” Hepatogastroenterology, Vol. 60, 2013, p. 127.
[21] L. Shi, et al., “Over-Expression of CKS1B Activates Both MEK/ERK and JAK/STAT3 Signaling Pathways and Promotes Myeloma Cell Drug-Resistance,” Oncotarget, Vol. 1, No. 1, 2010, pp. 22-33.
[22] K. E. Simon, H. H. Cha and G. L. Firestone, “Transforming Growth Factor Beta Down-Regulation of CKShs1 Transcripts in Growth-Inhibited Epithelial Cells,” Cell Growth & Differentiation, Vol. 6, No. 10, 1995, pp. 1261-1269.
[23] S. Suzuki, et al., “Up-Regulation of Cks1 and Skp2 with TNFalpha/NF-kappaB Signaling in Chronic Progressive Nephropathy,” Genes Cells, Vol. 16, No. 11, 2011, pp. 1110-1120. 10.1111/j.1365-2443.2011.01553.x
[24] Y. Zhang, et al., “Direct Cell Cycle Regulation by the Fibroblast Growth Factor Receptor (FGFR) Kinase through Phosphorylation-Dependent Release of Cks1 from FGFR Substrate 2,” Journal of Biological Chemistry, Vol. 279, No. 53, 2004, pp. 55348-55354.
[25] X. C. Wang, et al., “Overexpression of Cks1 Is Associated with Poor Survival by Inhibiting Apoptosis in Breast Cancer,” Journal of Cancer Research and Clinical Oncology, Vol. 135, No. 10, 2009, pp. 1393-1401.
[26] M. Frontini, et al., “The CDK Subunit CKS2 Counteracts CKS1 to Control Cyclin A/CDK2 Activity in Maintaining Replicative Fidelity and Neurodevelopment,” Genes & Development, Vol. 23, No. 2, 2012, pp. 356-370.
[27] V. Liberal, et al., “Cyclin-Dependent Kinase Subunit (Cks) 1 or Cks2 Overexpression Overrides the DNA Damage Response Barrier Triggered by Activated Oncoproteins,” Proceedings of the National Academy of Sciences of USA, Vol. 109, No. 8, 2012, pp. 2754-2759. BF00331653
[28] J. Hayles, S. Aves and P. Nurse, “Suc1 Is an Essential Gene Involved in Both the Cell Cycle and Growth in Fission Yeast,” EMBO Journal, Vol. 5, No. 12, 1986, pp. 3373-3379.
[29] J. Hayles, et al., “The Fission Yeast Cell Cycle Control Gene cdc2: Isolation of a Sequence suc1 That Suppresses cdc2 Mutant Function,” Molecular and General Genetics, Vol. 202, No. 2, 1986, pp. 291-293.
[30] S. I. Reed, et al., “Analysis of the Cdc28 Protein Kinase Complex by Dosage Suppression,” Journal of Cell Science Supplement, Vol. 12, 1989, pp. 29-37. _12.4
[31] A. S. Arvai, et al., “Crystal Structure of the Human Cell Cycle Protein CksHs1: Single Domain Fold with Similarity to Kinase N-Lobe Domain,” Journal of Molecular Biology, Vol. 249, No. 5, 1995, pp. 835-842.
[32] Y. Bourne, et al., “Crystal Structure and Mutational Analysis of the Human CDK2 Kinase Complex with Cell Cycle-Regulatory Protein CksHs1,” Cell, Vol. 84, No. 6, 1996, pp. 863-874. 10.1016/S0092-8674(00)81065-X
[33] J. A. Hadwiger, et al., “The Saccharomyces Cerevisiae CKS1 Gene, a Homolog of the Schizosaccharomyces Pombe suc1+ Gene, Encodes a Subunit of the Cdc28 Protein Kinase Complex,” Molecular and Cellular Biology, Vol. 9, No. 5, 1989, pp. 2034-2041.
[34] J. Hindley, et al., “Sucl+ Encodes a Predicted 13-Kilodalton Protein That Is Essential for Cell Viability and Is Directly Involved in the Division Cycle of Schizosaccharomyces Pombe,” Molecular and Cellular Biology, Vol. 7, No. 1, 1987, pp. 504-511.
[35] Y. Bourne, et al., “Crystal Structure and Mutational Analysis of the Saccharomyces cerevisiae Cell Cycle Regulatory Protein Cks1: Implications for Domain Swapping, Anion Binding and Protein Interactions,” Structure, Vol. 8, No. 8, 2000, pp. 841-850.
[36] N. Khazanovich, et al., “Crystal Structure of the Yeast Cell-Cycle Control Protein, P13suc1, in a Strand-Exchanged Dimmer,” Structure, Vol. 4, No. 3, 1996, pp. 299-309. S0969-2126(96)00034-2
[37] H. E. Richardson, et al., “Human cDNAs Encoding Homologs of the Small p34Cdc28/Cdc2-Associated Protein of Saccharomyces cerevisiae and Schizosaccharomyces pombe,” Genes & Development, Vol. 4, No. 8, 1990, pp. 1332-1344.
[38] A. Satyanarayana and P. Kaldis, “Mammalian Cell-Cycle Regulation: Several Cdks, Numerous Cyclins and Diverse Compensatory Mechanisms,” Oncogene, Vol. 28, No. 33, 2009, pp. 2925-2939.
[39] R. Bader, et al., “Folding and Fibril Formation of the Cell Cycle Protein Cks1,” The Journal of Biological Chemistry, Vol. 281, No. 27, 2006, pp. 18816-18824.
[40] A. S. Arvai, et al., “Crystallization and Preliminary Crystallographic Study of Human CksHs1: A Cell Cycle Regulatory Protein,” Proteins, Vol. 21, No. 1, 1995, pp. 70-73. prot.340210109
[41] D. Sitry, et al., “Three Different Binding Sites of Cks1 are Required for p27-Ubiquitin Ligation,” The Journal of Biological Chemistry, Vol. 277, No. 44, 2002, pp. 42233-42240. jbc.M205254200
[42] B. Hao, et al., “Structural Basis of the Cks1-Dependent Recognition of p27(Kip1) by the SCF(Skp2) Ubiquitin ligase,” Molecular Cell, Vol. 20, No. 1, 2005, pp. 9-19. j.molcel.2005.09.003
[43] W. Wang, et al., “Molecular and Biochemical Characterization of the Skp2-Cks1 Binding Interface,” The Journal of Biological Chemistry, Vol. 279, No. 49, 2004, pp. 51362-51369. 10.1074/jbc.M405944200
[44] L. Brizuela, G. Draetta and D. Beach, “p13suc1 Acts in the Fission Yeast Cell Division Cycle as a Component of the p34cdc2 Protein Kinase,” The EMBO Journal, Vol. 6, No. 11, 1987, pp. 3507-3514.
[45] D. Patra, et al., “The Xenopus Suc1/Cks Protein Promotes the Phosphorylation of G(2)/M Regulators,” The Journal of Biological Chemistry, Vol. 274, No. 52, 1999, pp. 36839-36842. 10.1074/jbc.274.52.36839
[46] M. Koivomagi, et al., “Cascades of Multisite Phosphorylation Control Sic1 Destruction at the Onset of S Phase,” Nature, Vol. 480, No. 7375, 2011, pp. 128-131.
[47] S. Xu, et al., “Substrate Recognition and Ubiquitination of SCFSkp2/Cks1 Ubiquitin-Protein Isopeptide Ligase,” The Journal of Biological Chemistry, Vol. 282, No. 21, 2007, pp. 15462-15470.
[48] A. Krishnan, S. A. Nair and M. R. Pillai, “Loss of Cks1 Homeostasis Deregulates Cell Division Cycle,” Journal of Cellular and Molecular Medicine, Vol. 14, No. 1-2, 2010, pp. 154-164.
[49] T. Bashir and M. Pagano, “Don’t Skip the G1 Phase: How APC/CCdh1 Keeps SCFSKP2 in Check. Cell Cycle, Vol. 3, No. 7, 2004, pp. 850-852.
[50] J. W. Harper, “Protein Destruction: Adapting Roles for Cks Proteins,” Current Biology, Vol. 11, No. 11, 2001, pp. R431-R435.
[51] A. Krishnan, S. A. Nair and M. R. Pillai, “Loss of Cks1 Homeostasis Deregulates Cell Division Cycle,” Journal of Cellular and Molecular Medicine, Vol. 14, No. 1-2, 2010, pp. 154-164.
[52] J. Pines, “Cell Cycle: Reaching for a Role for the Cks Proteins,” Current Biology, Vol. 6, No. 11, 1996, pp. 1399-1402.
[53] J. Bartek and J. Lukas, “p27 Destruction: Cks1 Pulls the Trigger,” Nature Cell Biology, Vol. 3, No. 4, 2001, pp. E95-E98.
[54] Y. Tang and S. I. Reed, “The Cdk-Associated Protein Cks1 Functions Both in G1 and G2 in Saccharomyces cerevisiae,” Genes & Development, Vol. 7, No. 5, 1993, pp. 822-832.
[55] B. A. Schulman, et al., “Insights into SCF Ubiquitin Ligases from the Structure of the Skp1-Skp2 Complex,” Nature, Vol. 408, No. 6810, 2000, pp. 381-386.
[56] G. Mulligan and T. Jacks, “The Retinoblastoma Gene Family: Cousins with Overlapping Interests,” Trends in Genetics, Vol. 14, No. 6, 1998, pp. 223-229.
[57] X. Mayol and X. Grana, “The p130 Pocket Protein: Keeping Order at Cell Cycle Exit/Re-Entrance Transitions,” Frontiers in Bioscience, Vol. 3, 1998, pp. d11-d24.
[58] D. Tedesco, J. Lukas and S. I. Reed, “The pRb-Related Protein p130 is Regulated by Phosphorylation-Dependent Proteolysis via the Protein-Ubiquitin Ligase SCF(Skp2),” Genes & Development, Vol. 16, No. 22, 2002, pp. 2946-2957.
[59] R. Wasch and D. Engelbert, “Anaphase-Promoting Complex-Dependent Proteolysis of Cell Cycle Regulators and Genomic Instability of Cancer Cells,” Oncogene, Vol. 24, No. 1, 2005, pp. 1-10.
[60] L. Song and M. Rape, “Regulated Degradation of Spindle Assembly Factors by the Anaphase-Promoting Complex,” Molecular Cell, Vol. 38, No. 3, 2010, pp. 369-382. j.molcel.2010.02.038
[61] A. M. Fry and H. Yamano, “APC/C-Mediated Degradation in Early Mitosis: How to Avoid Spindle Assembly Checkpoint Inhibition,” Cell Cycle, Vol. 5, No. 14, 2006, pp. 1487-1491.
[62] S. Kim and H. Yu, “Mutual Regulation between the Spindle Checkpoint and APC/C,” Seminars in Cell & Developmental Biology, Vol. 22, No. 6, 2011, pp. 551-558. 2011.03.008
[63] R. H. Chen, “Dual Inhibition of Cdc20 by the Spindle Checkpoint,” Journal of Biomedical Science, Vol. 14(4): 2007, pp. 475-479.
[64] J. Nilsson, et al., “The APC/C Maintains the Spindle Assembly Checkpoint by Targeting Cdc20 for Destruction,” Nature Cell Biology, Vol. 10, No. 12, 2008, pp. 1411-1420. 10.1038/ncb1799
[65] W. van Zon and R. M. Wolthuis, “Cyclin A and Nek2A: APC/C-Cdc20 Substrates Invisible to the Mitotic Spindle Checkpoint,” Biochemical Society Transactions, Vol. 38, 2010, pp. 72-77. 10.1042/BST0380072
[66] B. Di Fiore and J. Pines, “How Cyclin A Destruction Escapes the Spindle Assembly Checkpoint,” Nature Cell Biology, Vol. 190, No. 4, 2010, pp. 501-509.
[67] R. Wolthuis, et al., “Cdc20 and Cks Direct the Spindle Checkpoint-Independent Destruction of Cyclin A,” Molecular Cell, Vol. 30, No. 3, 2008, pp. 290-302.
[68] D. Patra and W. G. Dunphy, “Xe-p9, a Xenopus Suc1/ Cks Protein, Is Essential for the Cdc2-Dependent Phosphorylation of the Anaphase-Promoting Complex at Mitosis,” Genes & Development, Vol. 12, No. 16, 1998, pp. 2549-2559.
[69] D. Patra and W. G. Dunphy, “Xe-p9, a Xenopus Suc1/ Cks Homolog, Has Multiple Essential Roles in Cell Cycle Control,” Genes & Development, Vol. 10, No. 12, 1996, pp. 1503-1515.
[70] L. Westbrook, et al., “Cks1 Regulates Cdk1 Expression: A Novel Role during Mitotic Entry in Breast Cancer Cells,” Cancer Research, Vol. 67, No. 23, 2007, pp. 11393-11401. 0008-5472.CAN-06-4173
[71] H. S. Martinsson-Ahlzen, et al., “Cyclin-Dependent Kinase-Associated Proteins Cks1 and Cks2 Are Essential during Early Embryogenesis and for Cell Cycle Progression in Somatic Cells,” Molecular and Cellular Biology, Vol. 28, No. 18, 2008, pp. 5698-5709.
[72] Y. S. Tsai, et al., “RNA Silencing of Cks1 Induced G2/M Arrest and Apoptosis in Human Lung Cancer Cells,” IUBMB Life, Vol. 57, No. 8, 2005, pp. 583-589.
[73] A. Hoellein, et al., “Cks1 Promotion of S Phase Entry and Proliferation Is Independent of p27Kip1 Suppression,” Molecular and Cellular Biology, Vol. 32, No. 13, 2012, pp. 2416-2427.
[74] S. Chaves, et al., “Cks1, Cdk1, and the 19S Proteasome Collaborate to Regulate Gene Induction-Dependent Nucleosome Eviction in Yeast,” Molecular and Cellular Biology, Vol. 30, No. 22, 2010, pp. 5284-5294.
[75] R. Holic, et al., “Cks1 Activates Transcription by Binding to the Ubiquitylated Proteasome,” Molecular and Cellular Biology, Vol. 30, No. 15, 2010, pp. 3894-3901.
[76] M. C. Morris, et al., “Cks1-Dependent Proteasome Recruitment and Activation of CDC20 Transcription in Budding Yeast,” Nature, Vol. 423, No. 6943, 2003, pp. 1009-1013. nature01720
[77] V. P. Yu, et al., “A Kinase-Independent Function of Cks1 and Cdk1 in Regulation of Transcription,” Molecular Cell, Vol. 17, No. 1, 2005, pp. 145-151.
[78] D. J. Baker, et al., “Mitotic Regulation of the Anaphase-Promoting Complex,” Cellular and Molecular Life Sciences, Vol. 64, No. 5, 2007, pp. 589-600.
[79] L. J. Appleman, et al., “CD28 Costimulation Mediates Transcription of SKP2 and CKS1, the substrate Recognition Components of SCFSkp2 Ubiquitin Ligase That Leads p27kip1 to Degradation,” Cell Cycle, Vol. 5, No. 18, 2006, pp. 2123-2129.
[80] M. Dibb, et al., “The FOXM1-PLK1 Axis Is Commonly Upregulated in Oesophageal Adenocarcinoma,” British Journal of Cancer, Vol. 107, No. 10, 2012, pp. 1766-1775. bjc.2012.424
[81] U. B. Keller, et al., “Myc Targets Cks1 to Provoke the Suppression of p27Kip1, Proliferation and Lymphomagenesis,” The EMBO Journal, Vol. 26, No. 10, 2007, pp. 2562-2574. 10.1038/sj.emboj.7601691
[82] M. Mourot, et al., “The Influence of Follicle Size, FSHEnriched Maturation Medium, and Early Cleavage on Bovine Oocyte Maternal mRNA Levels,” Molecular Reproduction and Development, Vol. 73, No. 11, 2006, pp. 1367-1379.
[83] V. Petrovic, et al., “FoxM1 Regulates Growth Factor-Induced Expression of Kinase-Interacting Stathmin (KIS) to Promote Cell Cycle Progression,” The Journal of Biological Chemistry, Vol. 283, No. 1, 2008, pp. 453-460.
[84] N. Uehara, K. Yoshizawa and A. Tsubura, “Vorinostat Enhances Protein Stability of p27 and p21 through Negative Regulation of Skp2 and Cks1 in Human Breast Cancer Cells,” Oncology Reports, Vol. 28, No. 1, 2012, pp. 105-110.
[85] I. C. Wang, et al., “Forkhead Box M1 Regulates the Transcriptional Network of Genes Essential for Mitotic Progression and Genes Encoding the SCF (Skp2-Cks1) Ubiquitin Ligase,” Molecular and Cellular Biology, Vol. 25, No. 24, 2005, pp. 10875-10894. 10875-10894.2005
[86] W. Wang, et al., “Negative Regulation of SCFSkp2 Ubiquitin Ligase by TGF-Beta Signaling,” Oncogene, Vol. Vol. 23, No. 5, 2004, pp. 1064-1075.
[87] K. Rother, et al., “Expression of Cyclin-Dependent Kinase Subunit 1 (Cks1) Is Regulated during the Cell Cycle by a CDE/CHR Tandem Element and is Downregulated by p53 but Not by p63 or p73,” Cell Cycle, Vol. 6, No. 7, 2007, pp. 853-862.
[88] T. Bashir, et al., “Control of the SCF(Skp2-Cks1) Ubiquitin Ligase by the APC/C(Cdh1) Ubiquitin Ligase,” Nature, Vol. 428, No. 6979, 2004, pp. 190-193.
[89] D. J. Lenschow, T. L. Walunas and J. A. Bluestone, “CD28/B7 System of T Cell Costimulation,” Annual Review of Immunology, Vol. 14, 1996, pp. 233-258. immunol.14.1.233
[90] L. J. Appleman, et al., “CD28 Costimulation Mediates T Cell Expansion via IL-2-Independent and IL-2-Dependent Regulation of Cell Cycle Progression,” The Journal of Immunology, Vol. 164, No. 1, 2000, pp. 144-151.
[91] M. Okamura, et al., “The Possible Mechanism of Enhanced Carcinogenesis Induced by Genotoxic Carcinogens in rasH2 Mice,” Cancer Letters, Vol. 245, No. 1-2, 2007, pp. 321-330. 10.1016/j.canlet.2006.01.025
[92] E. S. Polinko and S. Strome, “Depletion of a Cks Homolog in C. Elegans Embryos Uncovers a Post-Metaphase Role in Both Meiosis and Mitosis,” Current Biology, Vol. 10, No. 22, 2000, p. 1471-1474.
[93] M. Ghorbani, et al., “Cks85A and Skp2 Interact to Maintain Diploidy and Promote Growth in Drosophila,” Developmental Biology, Vol. 358, No. 1, 2011, pp. 213-223. 10.1016/j.ydbio.2011.07.031
[94] H. Yang, et al., “Identification and Expression of the Amphioxus Cks1 Gene,” Cell Biology International, Vol. 29, No. 7, 2005, pp. 593-597.
[95] J. C. Mottram and K. M. Grant, “Leishmania Mexicana p12cks1, a Homologue of Fission Yeast p13suc1, Associates with a Stage-Regulated Histone H1 Kinase,” Biochemical Journal, Vol. 316 , 1996, pp. 833-839.
[96] P. Colas, F. Serras and A. E. Van Loon, “Microinjection of Suc1 Transcripts Delays the Cell Cycle Clock in Patella Vulgata Embryos,” The International Journal of Developmental Biology, Vol. 37, No. 4, 1993, pp. 589-594.
[97] V. Boudolf, et al., “Identification of Novel Cyclin-Dependent Kinases Interacting with the Cks1 Protein of Arabidopsis,” Journal of Experimental Botany, Vol. 52, No. 359, 2001, pp. 1381-1382.
[98] L. De Veylder, et al., “The Arabidopsis Cks1At Protein Binds the Cyclin-Dependent Kinases Cdc2aAt and Cdc2bAt,” FEBS Letters, Vol. 412, No. 3, 1997, pp. 446-452.
[99] V. L. De, et al., “CKS1At Overexpression in Arabidopsis thaliana Inhibits Growth by Reducing Meristem Size and Inhibiting Cell-Cycle Progression,” The Plant Journal, Vol. 25, No. 6, 2001, pp. 617-626.
[100] K. M. Grant, et al., “The Crk3 Gene of Leishmania Mexicana Encodes a Stage-Regulated cdc2-Related Histone H1 Kinase That Associates with p12,” The Journal of Biological Chemistry, Vol. 273, No. 17, 1998, pp. 10153-10159.
[101] N. J. Pearson, et al., “A Pre-Anaphase Role for a Cks/ Suc1 in Acentrosomal Spindle Formation of Drosophila Female Meiosis,” EMBO Reports, Vol. 6, No. 11, 2005, pp. 1058-1063.
[102] A. Swan, G. Barcelo and T. Schupbach, “Drosophila Cks30A Interacts with Cdk1 to Target Cyclin A for Destruction in the Female Germline,” Development, Vol. 132, No. 16, 2005, pp. 3669-3678.
[103] A. Swan and T. Schupbach, “Drosophila Female Meiosis and Embryonic Syncytial Mitosis Use Specialized Cks and CDC20 Proteins for Cyclin Destruction,” Cell Cycle, Vol. 4, No. 10, 2005, pp. 1332-1334.
[104] C. A. Auld, K. M. Fernandes and R. F. Morrison, “Skp2-Mediated p27(Kip1) Degradation during S/G2 Phase Progression of Adipocyte Hyperplasia,” Journal of Cellular Physiology, Vol. 211, No. 1, 2007, pp. 101-111.
[105] M. Radulovic, et al., “CKS Proteins Protect Mitochondrial Genome Integrity by Interacting with Mitochondrial Single-Stranded DNA-Binding Protein,” Molecular & Cellular Proteomics, Vol. 9, No. 1, 2010, pp. 145-152.
[106] R. M. Nagler, et al., “The Expression and Prognostic Significance of Cks1 in Salivary Cancer,” Cancer Investigation, Vol. 27, No. 5, 2009, pp. 512-520.
[107] M. Shapira, et al., “Alterations in the Expression of the Cell Cycle Regulatory Protein Cyclin Kinase Subunit 1 in Colorectal Carcinoma,” Cancer, Vol. 100, No. 8, 2004, pp. 1615-1621.
[108] D. D. Hershko and M. Shapira, “Prognostic Role of p27Kip1 Deregulation in Colorectal Cancer,” Cancer, Vol. 107, No. 4, 2006, pp. 668-675.
[109] M. Slotky, et al., “The Expression of the Ubiquitin Ligase Subunit Cks1 in Human Breast Cancer,” Breast Cancer Research, Vol. 7, No. 5, 2005, pp. R737-R744.
[110] L. Westbrook, et al., “High Cks1 Expression in Transgenic and Carcinogen-Initiated Mammary Tumors Is Not Always Accompanied by Reduction in p27Kip1,” International Journal of Oncology, Vol. 34, No. 5, 2009, pp. 1425-1431.
[111] N. Inui, et al., “High Expression of Cks1 in Human Non-Small Cell Lung Carcinomas,” Biochemical and Biophysical Research Communications, Vol. 303, No. 3, 2003, p. 978-984.
[112] S. Fredersdorf, et al., “High Level Expression of p27 (kip1) and Cyclin D1 in Some Human Breast Cancer Cells: Inverse Correlation between the Expression of p27 (kip1) and Degree of malignancy in human breast and colorectal cancers,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 12, 1997, pp. 6380-6385. pnas.94.12.6380
[113] T. H. Qiu, et al., “Global Expression Profiling Identifies Signatures of Tumor Virulence in MMTV-PyMT-Transgenic Mice: Correlation to Human Disease,” Cancer Research, Vol. 64, No. 17, 2004, pp. 5973-5981.
[114] Y. Hu, et al., “From Mice to Humans: Identification of Commonly Deregulated Genes in Mammary Cancer via Comparative SAGE Studies,” Cancer Research, Vol. 64, No. 21, 2004, pp. 7748-7755.
[115] S. Signoretti, et al., “Oncogenic Role of the Ubiquitin Ligase Subunit Skp2 in Human Breast Cancer,” Journal of Clinical Investigation, Vol. 110, No. 5, 2002, pp. 633-641.
[116] A. Krishnan, et al., “Fluoxetine Mediates G0/G1 Arrest by Inducing Functional Inhibition of Cyclin Dependent Kinase Subunit (CKS)1,” Biochemical Pharmacology, Vol. 75, No. 10, 2008, pp. 1924-1934.
[117] J. Jiang and D. Sliva, “Novel Medicinal Mushroom Blend Suppresses Growth and Invasiveness of Human Breast Cancer Cells,” International Journal of Oncology, Vol. 37, No. 6, 2010, pp. 1529-1536.
[118] E. Rico-Bautista, et al., “Chemical Genetics Approach to Restoring p27Kip1 Reveals Novel Compounds with Antiproliferative Activity in Prostate Cancer Cells,” BMC Biology, Vol. 8, 2010, p. 153.
[119] E. Rico-Bautista and D. A. Wolf, “Skipping Cancer: Small Molecule Inhibitors of SKP2-Mediated p27 Degradation,” Chemistry & Biology, Vol. 19, No. 12, 2012, pp. 1497-1498. 10.1016/j.chembiol.2012.12.001
[120] L. Wu, et al., “Specific Small Molecule Inhibitors of Skp2-Mediated p27 Degradation,” Chemistry & Biology, Vol. 19, No. 12, 2012, pp. 1515-1524.
[121] I. Urbanowicz-Kachnowicz, et al., “Ckshs Expression Is Linked to Cell Proliferation in Normal and Malignant Human Lymphoid Cells,” International Journal of Cancer, Vol. 82, No. 1, 1999, pp. 98-104.<98::AID-IJC17>3.0.CO;2-A
[122] S. de Vos, et al., “Cell cycle Alterations in the Blastoid Variant of Mantle Cell Lymphoma (MCL-BV) as Detected by Gene Expression Profiling of Mantle Cell Lymphoma (MCL) and MCL-BV,” Diagnostic Molecular Pathology, Vol. 12, No. 1, 2003, pp. 35-43.
[123] E. Bjorck, et al., “High Expression of Cyclin B1 Predicts a Favorable Outcome in Patients with Follicular Lymphoma,” Blood, Vol. 105, No. 7, 2005, pp. 2908-2915.
[124] N. Akyurek, et al., “Differential Expression of CKS-1B in Typical and Blastoid Variants of Mantle Cell Lymphoma,” Human Pathology, Vol. 41, No. 10, 2010, pp. 1448-1455. 10.1016/j.humpath.2010.04.001
[125] P. Zancai, et al., “Retinoic Acid Stabilizes p27Kip1 in EBV-Immortalized Lymphoblastoid B Cell Lines through Enhanced Proteasome-Dependent Degradation of the p45Skp2 and Cks1 Proteins,” Oncogene, Vol. 24, No. 15, 2005, pp. 2483-2494.
[126] S J. haughnessy, “Amplification and Overexpression of CKS1B at Chromosome Band 1q21 Is Associated with Reduced Levels of p27Kip1 and an Aggressive Clinical Course in Multiple Myeloma,” Hematology, Vol. 10, Suppl. 1, 2005, pp. 117-126. 512331390140
[127] H. Chang, et al., “Significant Increase of CKS1B Amplification from Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma and Plasma Cell Leukaemia as Demonstrated by Interphase Fluorescence in situ Hybridization,” British Journal of Haematology, Vol. 134, No. 6, 2006, p. 613-615.
[128] H. Chang, et al., “Multiple Myeloma Patients with CKS1B Gene Amplification Have a Shorter ProgressionFree Survival Post-Autologous Stem Cell Transplantation,” British Journal of Haematology, Vol. 135, No. 4, 2006, pp. 486-491. 2006.06325.x
[129] H. Chang, et al., “CKS1B Nuclear Expression Is Inversely Correlated with p27Kip1 Expression and Is Predictive of an Adverse Survival in Patients with Multiple Myeloma,” Haematologica, Vol. 95, No. 9, 2010, pp. 1542-1547.
[130] F. Zhan, et al., “CKS1B, Overexpressed in Aggressive Disease, Regulates Multiple Myeloma Growth and Survival through SKP2-and p27Kip1-Dependent and -Independent Mechanisms,” Blood, Vol. 109, No. 11, 2007, pp. 4995-5001.
[131] S. Kitajima, et al., “Role of Cks1 Overexpression in Oral Squamous Cell Carcinomas: Cooperation with Skp2 in Promoting p27 Degradation,” American Journal of Pathology, Vol. 165, No. 6, 2004, pp. 2147-2155.
[132] Y. Kudo, et al., “Down-Regulation of Cdk Inhibitor p27 in Oral Squamous Cell Carcinoma,” Oral Oncology, Vol. 41, No. 2, 2005, pp. 105-116.
[133] G. Martin-Ezquerra, et al., “CDC28 Protein Kinase Regulatory Subunit 1B (CKS1B) Expression and Genetic Status Analysis in Oral Squamous Cell Carcinoma,” Histology and Histopathology, Vol. 26, No. 1, 2011, pp. 71-77.
[134] J. J. Wang, et al., “Clinical Significance of Overexpressed Cyclin-Dependent Kinase Subunits 1 and 2 in Esophageal Carcinoma,” Diseases of the Esophagus, 2013, in press. dote.12013
[135] X. C. Wang, et al., “Overexpression of Cks1 Increases the Radiotherapy Resistance of Esophageal Squamous Cell Carcinoma,” Journal of Radiation Research, Vol. 53, No. 1, 2012, pp. 72-78.
[136] T. A. Masuda, et al., “Cyclin-Dependent Kinase 1 Gene Expression Is Associated with Poor Prognosis in Gastric Carcinoma,” Clinical Cancer Research, Vol. 9, No. 15, 2003, pp. 5693-5698.
[137] S. H. Li, et al., “Skp2 Is an Independent Prognosticator of Gallbladder Carcinoma among p27(Kip1)-Interacting Cell Cycle Regulators: An Immunohistochemical Study of 62 Cases by Tissue Microarray,” Modern Pathology, Vol. 20, No. 4, 2007, pp. 497-507.
[138] C. W. Huang, et al., “CKS1B Overexpression Implicates Clinical Aggressiveness of Hepatocellular Carcinomas But Not p27(Kip1) Protein Turnover: An Independent Prognosticator with Potential p27 (Kip1)-Independent Oncogenic Attributes?” Annals of Surgical Oncology, Vol. 17, No. 3, 2010, pp. 907-922.
[139] D. F. Calvisi, et al., “SKP2 and CKS1 Promote Degradation of Cell Cycle Regulators and Are Associated with Hepatocellular Carcinoma Prognosis,” Gastroenterology, Vol. 137, No. 5, 2009, pp. 1816-1826.
[140] D. F. Calvisi, et al., “The Degradation of Cell Cycle Regulators by SKP2/CKS1 Ubiquitin Ligase Is Genetically Controlled in Rodent Liver Cancer and Contributes to Determine the Susceptibility to The Disease,” International Journal of Cancer, Vol. 126, No. 5, 2010, pp. 1275-1281.
[141] F. Feo, M. Frau and R. M. Pascale, “Interaction of Major Genes Predisposing to Hepatocellular Carcinoma with Genes Encoding Signal Transduction Pathways Influences Tumor Phenotype and Prognosis,” World Journal of Gastroenterology, Vol. 14, No. 43, 2008, pp. 6601-6615.
[142] F. Feo, et al., “Genetic and Epigenetic Control of Molecular Alterations in Hepatocellular Carcinoma,” Experimental Biology and Medicine, Vol. 234, No. 7, 2009, pp. 726-736. 10.3181/0901-MR-40
[143] K. T. Huang, et al., “Estrogen and Progesterone Regulate p27kip1 Levels via the Ubiquitin-Proteasome System: Pathogenic and Therapeutic Implications for Endometrial Cancer,” PLoS ONE, Vol. 7, No. 9, 2012, Article ID: e46072.
[144] V. Ouellet, et al., “Discrimination between Serous Low Malignant Potential and Invasive Epithelial Ovarian Tumors Using Molecular Profiling,” Oncogene, Vol. 24, No. 29, 2005, pp. 4672-4687.
[145] V. Ouellet, et al., “Tissue Array Analysis of Expression Microarray Candidates Identifies Markers Associated with Tumor Grade and Outcome in Serous Epithelial Ovarian Cancer,” International Journal of Cancer, Vol. 119, No. 3, 2006, pp. 599-607.
[146] S. Yamamoto, et al., “Cumulative Alterations of p27-Related Cell-Cycle Regulators in the Development of Endometriosis-Associated Ovarian Clear Cell Adenocarcinoma,” Histopathology, Vol. 56, No. 6, 2010, pp. 740-749.
[147] S. Yamamoto, et al., “Aberrant Expression of p27(Kip1)-Interacting Cell-Cycle Regulatory Proteins in Ovarian Clear Cell Carcinomas and Their Precursors with Special Consideration of Two Distinct Multistage Clear Cell Carcinogenetic Pathways,” Virchows Arch, Vol. 455, No. 5, 2009, pp. 413-422.
[148] Y. Lan, et al., “Aberrant Expression of Cks1 and Cks2 Contributes to Prostate Tumorigenesis by Promoting Proliferation and Inhibiting Programmed Cell Death,” International Journal of Cancer, Vol. 123, No. 3, 2008, pp. 543-551.
[149] K. Miyai, et al., “Altered Expression of p27(Kip1)-Inter-Acting Cell-Cycle Regulators in the Adult Testicular Germ Cell Tumors: Potential Role in Tumor Development and Histological Progression,” APMIS, Vol. 120, No. 11, 2012, pp. 890-900.
[150] V. G. Zolota, et al., “Histologic-Type Specific Role of Cell Cycle Regulators in Non-Small Cell Lung Carcinoma,” Journal of Surgical Research, 164, No. 2, 2010, pp. 256-265.
[151] R. Salgado, et al., “CKS1B Amplification Is a Frequent Event in Cutaneous Squamous Cell Carcinoma with Aggressive Clinical Behaviour,” Genes, Chromosomes and Cancer, Vol. 49, No. 11, 2010, pp. 1054-1061.
[152] K. Kawakami, et al., “Increased SKP2 and CKS1 Gene Expression Contributes to the Progression of Human urothelial Carcinoma,” Journal of Urology, Vol. 178, No. 1, 2007, pp. 301-307.
[153] Z. Liu, et al., “Prognostic Implication of p27Kip1, Skp2 and Cks1 Expression in Renal Cell Carcinoma: A Tissue Microarray Study,” Journal of Experimental & Clinical Cancer Research, Vol. 27, 2008, p. 51.
[154] D. M. Kokkinakis, et al., “Modulation of Gene Expression in Human Central Nervous System Tumors under Methionine Deprivation-Induced Stress,” Cancer Research, Vol. 64, No. 20, 2004, pp. 7513-7525.
[155] H. Halfter, et al., “Oncostatin M Induces Growth Arrest by Inhibition of Skp2, Cks1, and Cyclin A Expression and Induced p21 Expression,” Cancer Research, Vol. 66, No. 13, 2006, pp. 6530-6539.
[156] R. Lin, et al., “Inhibition of F-Box Protein p45(SKP2) Expression and Stabilization of Cyclin-Dependent Kinase Inhibitor p27(KIP1) in Vitamin D Analog-Treated Cancer Cells,” Endocrinology, Vol. 144, No. 3, 2003, pp. 749-753.
[157] D. M. Gascoyne, et al., “Loss of Mitotic Spindle Checkpoint Activity Predisposes to Chromosomal Instability at Early Stages of Fibrosarcoma Development,” Cell Cycle, Vol. 2, No. 3, 2003, pp. 238-245.
[158] H. Y. Huang, et al., “Skp2 Overexpression Is Highly Representative of Intrinsic Biological Aggressiveness and Independently Associated with Poor Prognosis in Primary Localized Myxofibrosarcomas,” Clinical Cancer Research, Vol. 12, No. 2, 2006, pp. 487-498.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.