Modulation of a P-TEFb Functional Equilibrium for the Global Control of Cell Growth and Differentiation

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2006 Sep 19

PMID 16980611

Citations 73

Authors

Nanhai He

Andrea C Pezda

Qiang Zhou

Affiliations

Soon will be listed here.

Abstract

P-TEFb phosphorylates RNA polymerase II and negative elongation factors to stimulate general transcriptional elongation. It is kept in a functional equilibrium through alternately interacting with its positive (the Brd4 protein) and negative (the HEXIM1 protein and 7SK snRNA) regulators. To investigate the physiological significance of this phenomenon, we analyzed the responses of HeLa cells and murine erythroleukemia cells (MELC) to hexamethylene bisacetamide (HMBA), which inhibits growth and induces differentiation of many cell types. For both cell types, an efficient, albeit temporary disruption of the 7SK-HEXIM1-P-TEFb snRNP and enhanced formation of the Brd4-P-TEFb complex occurred soon after the treatment started. When the P-TEFb-dependent HEXIM1 expression markedly increased as the treatment continued, the abundant HEXIM1 pushed the P-TEFb equilibrium back toward the 7SK/HEXIM1-bound state. For HeLa cells, as HMBA produced only a minor, temporary effect on their growth, the equilibrium gradually returned to its pretreatment level. In contrast, long-term treatment of MELC induced terminal division and differentiation. Concurrently, the P-TEFb equilibrium was shifted overwhelmingly toward the 7SK snRNP side. Together, these data link the P-TEFb equilibrium to the intracellular transcriptional demand and proliferative/differentiated states of cells.

Citing Articles

Bird's eye view of natural products for the development of new anti-HIV agents: Understanding from a therapeutic viewpoint.

Al Amin M, Nafady M, Zehravi M, Sweilam S, Kumar K, Akiful Haque M Animal Model Exp Med. 2025; 8(3):441-457.

PMID: 39921221 PMC: 11904116. DOI: 10.1002/ame2.12563.

HMBA ameliorates obesity by MYH9- and ACTG1-dependent regulation of hypothalamic neuropeptides.

Park S, Oh S, Kim N, Kim E EMBO Mol Med. 2023; 15(12):e18024.

PMID: 37984341 PMC: 10701615. DOI: 10.15252/emmm.202318024.

HEXIM1 is an essential transcription regulator during human erythropoiesis.

Lv X, Murphy K, Murphy Z, Getman M, Rahman N, Nakamura Y Blood. 2023; 142(25):2198-2215.

PMID: 37738561 PMC: 10733840. DOI: 10.1182/blood.2022019495.

P-TEFb: The master regulator of transcription elongation.

Fujinaga K, Huang F, Peterlin B Mol Cell. 2023; 83(3):393-403.

PMID: 36599353 PMC: 9898187. DOI: 10.1016/j.molcel.2022.12.006.

Relieving DYRK1A repression of MKL1 confers an adult-like phenotype to human infantile megakaryocytes.

Elagib K, Brock A, Clementelli C, Mosoyan G, Delehanty L, Sahu R J Clin Invest. 2022; 132(19).

PMID: 35925681 PMC: 9525118. DOI: 10.1172/JCI154839.

References

Siegel D, Zhang X, Feinman R, Teitz T, Zelenetz A, Richon V . Hexamethylene bisacetamide induces programmed cell death (apoptosis) and down-regulates BCL-2 expression in human myeloma cells. Proc Natl Acad Sci U S A. 1998; 95(1):162-6. PMC: 18160. DOI: 10.1073/pnas.95.1.162. View

Marks P, Richon V, Rifkind R . Cell cycle regulatory proteins are targets for induced differentiation of transformed cells: Molecular and clinical studies employing hybrid polar compounds. Int J Hematol. 1996; 63(1):1-17. DOI: 10.1016/0925-5710(95)00428-9. View

Barboric M, Peterlin B . A new paradigm in eukaryotic biology: HIV Tat and the control of transcriptional elongation. PLoS Biol. 2005; 3(2):e76. PMC: 548956. DOI: 10.1371/journal.pbio.0030076. View

Yik J, Chen R, Pezda A, Zhou Q . Compensatory contributions of HEXIM1 and HEXIM2 in maintaining the balance of active and inactive positive transcription elongation factor b complexes for control of transcription. J Biol Chem. 2005; 280(16):16368-76. DOI: 10.1074/jbc.M500912200. View

Byers S, Price J, Cooper J, Li Q, Price D . HEXIM2, a HEXIM1-related protein, regulates positive transcription elongation factor b through association with 7SK. J Biol Chem. 2005; 280(16):16360-7. DOI: 10.1074/jbc.M500424200. View

Li Q, Price J, Byers S, Cheng D, Peng J, Price D . Analysis of the large inactive P-TEFb complex indicates that it contains one 7SK molecule, a dimer of HEXIM1 or HEXIM2, and two P-TEFb molecules containing Cdk9 phosphorylated at threonine 186. J Biol Chem. 2005; 280(31):28819-26. DOI: 10.1074/jbc.M502712200. View

Jang M, Mochizuki K, Zhou M, Jeong H, Brady J, Ozato K . The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell. 2005; 19(4):523-34. DOI: 10.1016/j.molcel.2005.06.027. View

Yang Z, Yik J, Chen R, He N, Jang M, Ozato K . Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell. 2005; 19(4):535-45. DOI: 10.1016/j.molcel.2005.06.029. View

De Falco G, Bellan C, DAmuri A, Angeloni G, Leucci E, Giordano A . Cdk9 regulates neural differentiation and its expression correlates with the differentiation grade of neuroblastoma and PNET tumors. Cancer Biol Ther. 2005; 4(3):277-81. DOI: 10.4161/cbt.4.3.1497. View

10.

Turano M, Napolitano G, Dulac C, Majello B, Bensaude O, Lania L . Increased HEXIM1 expression during erythroleukemia and neuroblastoma cell differentiation. J Cell Physiol. 2005; 206(3):603-10. DOI: 10.1002/jcp.20502. View

11.

Chen R, Yang Z, Zhou Q . Phosphorylated positive transcription elongation factor b (P-TEFb) is tagged for inhibition through association with 7SK snRNA. J Biol Chem. 2003; 279(6):4153-60. DOI: 10.1074/jbc.M310044200. View

12.

Price D . P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol Cell Biol. 2000; 20(8):2629-34. PMC: 85478. DOI: 10.1128/MCB.20.8.2629-2634.2000. View

13.

Chao S, Price D . Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem. 2001; 276(34):31793-9. DOI: 10.1074/jbc.M102306200. View

14.

Yang Z, Zhu Q, Luo K, Zhou Q . The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature. 2001; 414(6861):317-22. DOI: 10.1038/35104575. View

15.

Nguyen V, Kiss T, Michels A, Bensaude O . 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature. 2001; 414(6861):322-5. DOI: 10.1038/35104581. View

16.

Houzelstein D, Bullock S, Lynch D, Grigorieva E, Wilson V, Beddington R . Growth and early postimplantation defects in mice deficient for the bromodomain-containing protein Brd4. Mol Cell Biol. 2002; 22(11):3794-802. PMC: 133820. DOI: 10.1128/MCB.22.11.3794-3802.2002. View

17.

Shim E, Walker A, Shi Y, Blackwell T . CDK-9/cyclin T (P-TEFb) is required in two postinitiation pathways for transcription in the C. elegans embryo. Genes Dev. 2002; 16(16):2135-46. PMC: 186450. DOI: 10.1101/gad.999002. View

18.

Sano M, Abdellatif M, Oh H, Xie M, Bagella L, Giordano A . Activation and function of cyclin T-Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy. Nat Med. 2002; 8(11):1310-7. DOI: 10.1038/nm778. View

19.

De Falco G, Giordano A . CDK9: from basal transcription to cancer and AIDS. Cancer Biol Ther. 2002; 1(4):342-7. View

20.

Michels A, Nguyen V, Fraldi A, Labas V, Edwards M, Bonnet F . MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner. Mol Cell Biol. 2003; 23(14):4859-69. PMC: 162212. DOI: 10.1128/MCB.23.14.4859-4869.2003. View