Cyclin-dependent kinase 7 explained

Cyclin-dependent kinase 7, or cell division protein kinase 7, is an enzyme that in humans is encoded by the CDK7 gene.^[1]

The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression.

This protein forms a trimeric complex with cyclin H and MAT1, which functions as a Cdk-activating kinase (CAK). It is an essential component of the transcription factor TFIIH, that is involved in transcription initiation and DNA repair. This protein is thought to serve as a direct link between the regulation of transcription and the cell cycle.^[2]

Clinical significance e.g. cancer

Given that CDK7 is involved in two important regulation roles, it's expected that CDK7 regulation may play a role in cancerous cells. Cells from breast cancer tumors were found to have elevated levels of CDK7 and Cyclin H when compared to normal breast cells. It was also found that the higher levels were generally found in ER-positive breast cancer. Together, these findings indicate that CDK7 therapy might make sense for some breast cancer patients.^[3] Further confirming these findings, recent research indicates that inhibition of CDK7 may be an effective therapy for HER2-positive breast cancers, even overcoming therapeutic resistance. THZ1 was tested on HER2-positive breast cancer cells and exhibited high potency for the cells regardless of their sensitivity to HER2 inhibitors. This finding was demonstrated in vivo, where inhibition of HER2 and CDK7 resulted in tumor regression in therapeutically resistant HER2+ xenograft models.^[4]

Inhibitors

The growth suppressor p53 has been shown to interact with cyclin H both in vitro and in vivo. Addition of wild type p53 was found to heavily downregulated CAK activity, resulting in decreased phosphorylation of both CDK2 and CTD by CDK7. Mutant p53 was unable to downregulate CDK7 activity and mutant p21 had no effect on downregulation, indicating that p53 is responsible for negative regulation of CDK7.^[5]

In 2017 CT7001, an oral CDK7 inhibitor, started a phase 1 clinical trial.^[6]

THZ1 is an inhibitor for CDK7 that selectively forms a covalent bond with the CDK7-cycH-MAT1 complex. This selectivity stems from forming a bond at C312, which is unique to CDK7 within the CDK family. CDK12 and CDK13 could also be inhibited using THZ1 (but at higher concentrations) because they have similar structures in the region surrounding C312.^[7] It was found that treatment of 250 nM THZ1 was sufficient to inhibit global transcription and that cancer cell lines were sensitive to much lower concentrations, opening up further research into the efficacy of using THZ1 as a component of cancer therapy, as described above.

In renal cell carcinoma (RCC), the expression of CDK7 was significantly higher in the advanced stage tumors. Besides, the overall survival was significantly shorter in patients with higher CDK7 expression in the tumors. These results suggest that CDK7 may be a potential target for overcoming RCC.^[8]

Based on molecular docking results, Ligands-3, 5, 14, and 16 were screened among 17 different Pyrrolone-fused benzosuberene compounds as potent and specific inhibitors without any cross-reactivity against different CDK isoforms. Analysis of MD simulations and MM-PBSA studies, revealed the binding energy profiles of all the selected complexes. Selected ligands performed better than the experimental drug candidate (Roscovitine). Ligands-3 and 14 show specificity for CDK7. These ligands are expected to possess lower risk of side effects due to their natural origin.^[9]

In urothelial carcinoma (UC), CDK7 expression is increased in bladder cancer tissues, especially in patients with chemoresistance. CDK7 inhibition-related cancer stemness suppression is a potential therapeutic strategy for both chemonaïve and chemoresistant UC.^[10]

Interactions

Cyclin-dependent kinase 7 has been shown to interact with:

• Androgen receptor,^[11]
• Cyclin H,^{[12] [13]}
• GTF2H1,^[14]
• MNAT1,^[15]
• P53,^{[16] [5]}
• SUPT5H,^[13] and
• XPB.^{[17] [18] [19]}

See also

• Cyclin-dependent kinase
• CDK7 pathway

Further reading

• Jeang KT . Tat, Tat-associated kinase, and transcription . Journal of Biomedical Science . 5 . 1 . 24–7 . 1998 . 9570510 . 10.1007/BF02253352 .
• Yankulov K, Bentley D . Transcriptional control: Tat cofactors and transcriptional elongation . Current Biology . 8 . 13 . R447-9 . June 1998 . 9651670 . 10.1016/S0960-9822(98)70289-1 . 15480646 . free . 1998CBio....8.R447Y .
• Shiekhattar R, Mermelstein F, Fisher RP, Drapkin R, Dynlacht B, Wessling HC, Morgan DO, Reinberg D . 6 . Cdk-activating kinase complex is a component of human transcription factor TFIIH . Nature . 374 . 6519 . 283–7 . March 1995 . 7533895 . 10.1038/374283a0 . 1995Natur.374..283S . 4282418 .
• Aprelikova O, Xiong Y, Liu ET . Both p16 and p21 families of cyclin-dependent kinase (CDK) inhibitors block the phosphorylation of cyclin-dependent kinases by the CDK-activating kinase . The Journal of Biological Chemistry . 270 . 31 . 18195–7 . August 1995 . 7629134 . 10.1074/jbc.270.31.18195 . free .
• Serizawa H, Mäkelä TP, Conaway JW, Conaway RC, Weinberg RA, Young RA . Association of Cdk-activating kinase subunits with transcription factor TFIIH . Nature . 374 . 6519 . 280–2 . March 1995 . 7885450 . 10.1038/374280a0 . 1995Natur.374..280S . 4321212 .
• Tassan JP, Schultz SJ, Bartek J, Nigg EA . Cell cycle analysis of the activity, subcellular localization, and subunit composition of human CAK (CDK-activating kinase) . The Journal of Cell Biology . 127 . 2 . 467–78 . October 1994 . 7929589 . 2120215 . 10.1083/jcb.127.2.467 .
• Darbon JM, Devault A, Taviaux S, Fesquet D, Martinez AM, Galas S, Cavadore JC, Dorée M, Blanchard JM . 6 . Cloning, expression and subcellular localization of the human homolog of p40MO15 catalytic subunit of cdk-activating kinase . Oncogene . 9 . 11 . 3127–38 . November 1994 . 7936635 .
• Williams RT, Wu L, Carbonaro-Hall DA, Hall FL . Identification, assay, and purification of a Cdc2-activating threonine-161 protein kinase from human cells . Archives of Biochemistry and Biophysics . 314 . 1 . 99–106 . October 1994 . 7944411 . 10.1006/abbi.1994.1416 .
• Mäkelä TP, Tassan JP, Nigg EA, Frutiger S, Hughes GJ, Weinberg RA . A cyclin associated with the CDK-activating kinase MO15 . Nature . 371 . 6494 . 254–7 . September 1994 . 8078587 . 10.1038/371254a0 . 1994Natur.371..254M . 4369898 .
• Levedakou EN, He M, Baptist EW, Craven RJ, Cance WG, Welcsh PL, Simmons A, Naylor SL, Leach RJ, Lewis TB . 6 . Two novel human serine/threonine kinases with homologies to the cell cycle regulating Xenopus MO15, and NIMA kinases: cloning and characterization of their expression pattern . Oncogene . 9 . 7 . 1977–88 . July 1994 . 8208544 .
• Wu L, Yee A, Liu L, Carbonaro-Hall D, Venkatesan N, Tolo VT, Hall FL . Molecular cloning of the human CAK1 gene encoding a cyclin-dependent kinase-activating kinase . Oncogene . 9 . 7 . 2089–96 . July 1994 . 8208556 .
• Yee A, Nichols MA, Wu L, Hall FL, Kobayashi R, Xiong Y . Molecular cloning of CDK7-associated human MAT1, a cyclin-dependent kinase-activating kinase (CAK) assembly factor . Cancer Research . 55 . 24 . 6058–62 . December 1995 . 8521393 .
• Blau J, Xiao H, McCracken S, O'Hare P, Greenblatt J, Bentley D . Three functional classes of transcriptional activation domain . Molecular and Cellular Biology . 16 . 5 . 2044–55 . May 1996 . 8628270 . 231191 . 10.1128/MCB.16.5.2044 .
• Bartkova J, Zemanova M, Bartek J . Expression of CDK7/CAK in normal and tumor cells of diverse histogenesis, cell-cycle position and differentiation . International Journal of Cancer . 66 . 6 . 732–7 . June 1996 . 8647641 . 10.1002/(SICI)1097-0215(19960611)66:6<732::AID-IJC4>3.0.CO;2-0 . 7244269 . free .
• Reardon JT, Ge H, Gibbs E, Sancar A, Hurwitz J, Pan ZQ . Isolation and characterization of two human transcription factor IIH (TFIIH)-related complexes: ERCC2/CAK and TFIIH . Proceedings of the National Academy of Sciences of the United States of America . 93 . 13 . 6482–7 . June 1996 . 8692841 . 39049 . 10.1073/pnas.93.13.6482 . 1996PNAS...93.6482R . free .
• Drapkin R, Le Roy G, Cho H, Akoulitchev S, Reinberg D . Human cyclin-dependent kinase-activating kinase exists in three distinct complexes . Proceedings of the National Academy of Sciences of the United States of America . 93 . 13 . 6488–93 . June 1996 . 8692842 . 39050 . 10.1073/pnas.93.13.6488 . 1996PNAS...93.6488D . free .
• Zhou Q, Sharp PA . Tat-SF1: cofactor for stimulation of transcriptional elongation by HIV-1 Tat . Science . 274 . 5287 . 605–10 . October 1996 . 8849451 . 10.1126/science.274.5287.605 . 1996Sci...274..605Z . 13266489 .
• Parada CA, Roeder RG . Enhanced processivity of RNA polymerase II triggered by Tat-induced phosphorylation of its carboxy-terminal domain . Nature . 384 . 6607 . 375–8 . November 1996 . 8934526 . 10.1038/384375a0 . 1996Natur.384..375P . 4278432 .
• Richard Gaynor. García-Martínez LF, Ivanov D, Gaynor RB . Association of Tat with purified HIV-1 and HIV-2 transcription preinitiation complexes . The Journal of Biological Chemistry . 272 . 11 . 6951–8 . March 1997 . 9054383 . 10.1074/jbc.272.11.6951 . free .

Notes and References

1. Fisher RP, Morgan DO . A novel cyclin associates with MO15/CDK7 to form the CDK-activating kinase . Cell . 78 . 4 . 713–24 . August 1994 . 8069918 . 10.1016/0092-8674(94)90535-5 . 2996948 .
2. Web site: Entrez Gene: CDK7 cyclin-dependent kinase 7 (MO15 homolog, Xenopus laevis, cdk-activating kinase).
3. Patel H, Abduljabbar R, Lai CF, Periyasamy M, Harrod A, Gemma C, Steel JH, Patel N, Busonero C, Jerjees D, Remenyi J, Smith S, Gomm JJ, Magnani L, Győrffy B, Jones LJ, Fuller-Pace F, Shousha S, Buluwela L, Rakha EA, Ellis IO, Coombes RC, Ali S . 6 . Expression of CDK7, Cyclin H, and MAT1 Is Elevated in Breast Cancer and Is Prognostic in Estrogen Receptor-Positive Breast Cancer . Clinical Cancer Research . 22 . 23 . 5929–5938 . December 2016 . 27301701 . 5293170 . 10.1158/1078-0432.CCR-15-1104 .
4. Sun B, Mason S, Wilson RC, Hazard SE, Wang Y, Fang R, Wang Q, Yeh ES, Yang M, Roberts TM, Zhao JJ, Wang Q . 6 . Inhibition of the transcriptional kinase CDK7 overcomes therapeutic resistance in HER2-positive breast cancers . Oncogene . 39 . 1 . 50–63 . January 2020 . 31462705 . 10.1038/s41388-019-0953-9 . free . 6937212 .
5. Schneider E, Montenarh M, Wagner P . Regulation of CAK kinase activity by p53 . Oncogene . 17 . 21 . 2733–41 . November 1998 . 9840937 . 10.1038/sj.onc.1202504 . 6281777 .
6. https://www.evotec.com/en/invest/news--announcements/press-releases/p/carrick-therapeutics-announces-first-patient-dosed-in-phase-1-clinical-trial-of-its-oral-cdk7-inhibitor-ct7001-5517 ...first patient dosed in phase 1 clinical trial of its oral CDK7 inhibitor: CT7001 2017
7. Kwiatkowski N . etal . 2014 . Targeting transcription regulation in cancer with a covalent CDK7 inhibitor . Nature . 511 . 7511. 616–20 . 10.1038/nature13393 . 25043025 . 4244910 . 2014Natur.511..616K .
8. Chow PM, Liu SH, Chang YW, Kuo KL, Lin WC, Huang KH . The covalent CDK7 inhibitor THZ1 enhances temsirolimus-induced cytotoxicity via autophagy suppression in human renal cell carcinoma . Cancer Letters . 471 . 27–37 . February 2020 . 31812697 . 10.1016/j.canlet.2019.12.005 . 208956241 .
9. Singh R, Bhardwaj VK, Das P, Purohit R . Natural analogues inhibiting selective cyclin-dependent kinase protein isoforms: a computational perspective . Journal of Biomolecular Structure and Dynamics . 38 . 17 . November 2019 . 5126–5135 . 3176087 . 10.1080/07391102.2019.1696709 . 208276454 .
10. Chow PM, Chang YW, Kuo KL, Lin WC, Liu SH, Huang KH . CDK7 Inhibition by THZ1 Suppresses Cancer Stemness in both Chemonaïve and Chemoresistant Urothelial Carcinoma via the Hedgehog Signaling Pathway . Cancer Letters . 507 . 70–79 . June 2021 . 33741425 . 10.1016/j.canlet.2021.03.012 . 232299392 . 0304-3835 .
11. Lee DK, Duan HO, Chang C . From androgen receptor to the general transcription factor TFIIH. Identification of cdk activating kinase (CAK) as an androgen receptor NH(2)-terminal associated coactivator . The Journal of Biological Chemistry . 275 . 13 . 9308–13 . March 2000 . 10734072 . 10.1074/jbc.275.13.9308 . free.
12. Mäkelä TP, Tassan JP, Nigg EA, Frutiger S, Hughes GJ, Weinberg RA . A cyclin associated with the CDK-activating kinase MO15 . Nature . 371 . 6494 . 254–7 . September 1994 . 8078587 . 10.1038/371254a0 . 1994Natur.371..254M . 4369898 .
13. Garber ME, Mayall TP, Suess EM, Meisenhelder J, Thompson NE, Jones KA . CDK9 autophosphorylation regulates high-affinity binding of the human immunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA . Molecular and Cellular Biology . 20 . 18 . 6958–69 . September 2000 . 10958691 . 88771 . 10.1128/mcb.20.18.6958-6969.2000 .
14. Shiekhattar R, Mermelstein F, Fisher RP, Drapkin R, Dynlacht B, Wessling HC, Morgan DO, Reinberg D . 6 . Cdk-activating kinase complex is a component of human transcription factor TFIIH . Nature . 374 . 6519 . 283–7 . March 1995 . 7533895 . 10.1038/374283a0 . 1995Natur.374..283S . 4282418 .
15. Talukder AH, Mishra SK, Mandal M, Balasenthil S, Mehta S, Sahin AA, Barnes CJ, Kumar R . 6 . MTA1 interacts with MAT1, a cyclin-dependent kinase-activating kinase complex ring finger factor, and regulates estrogen receptor transactivation functions . The Journal of Biological Chemistry . 278 . 13 . 11676–85 . March 2003 . 12527756 . 10.1074/jbc.M209570200 . free .
16. Ko LJ, Shieh SY, Chen X, Jayaraman L, Tamai K, Taya Y, Prives C, Pan ZQ . 6 . p53 is phosphorylated by CDK7-cyclin H in a p36MAT1-dependent manner . Molecular and Cellular Biology . 17 . 12 . 7220–9 . December 1997 . 9372954 . 232579 . 10.1128/mcb.17.12.7220 .
17. Giglia-Mari G, Coin F, Ranish JA, Hoogstraten D, Theil A, Wijgers N, Jaspers NG, Raams A, Argentini M, van der Spek PJ, Botta E, Stefanini M, Egly JM, Aebersold R, Hoeijmakers JH, Vermeulen W . 6 . A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A . Nature Genetics . 36 . 7 . 714–9 . July 2004 . 15220921 . 10.1038/ng1387 . free .
18. Rossignol M, Kolb-Cheynel I, Egly JM . Substrate specificity of the cdk-activating kinase (CAK) is altered upon association with TFIIH . The EMBO Journal . 16 . 7 . 1628–37 . April 1997 . 9130708 . 1169767 . 10.1093/emboj/16.7.1628 .
19. Yee A, Nichols MA, Wu L, Hall FL, Kobayashi R, Xiong Y . Molecular cloning of CDK7-associated human MAT1, a cyclin-dependent kinase-activating kinase (CAK) assembly factor . Cancer Research . 55 . 24 . 6058–62 . December 1995 . 8521393 .