Developmental regulators containing the I-mfa domain interact with T cyclins and Tat and modulate transcription.
Positive transcription elongation factor b (P-TEFb) complexes, composed of cyclin-dependent kinase 9 (CDK9) and cyclin T1 or T2, are engaged by many cellular transcription regulators that activate or inhibit transcription from specific promoters. The related I-mfa (inhibitor of MyoD family a) and HIC (human I-mfa-domain-containing) proteins function in myogenic differentiation and embryonic development by participating in the Wnt signaling pathway. We report that I-mfa is a novel regulator of P-TEFb. Both HIC and I-mfa interact through their homologous I-mfa domains with cyclin T1 and T2 at two binding sites. One site is the regulatory histidine-rich domain that interacts with CDK9 substrates including RNA polymerase II. The second site contains a lysine and arginine-rich motif that is highly conserved between the two T cyclins. This site overlaps and includes the previously identified Tat/TAR recognition motif of cyclin T1 required for activation of human immunodeficiency virus type 1 (HIV-1) transcription. HIC and I-mfa can serve as substrates for P-TEFb. Their I-mfa domains also bind the activation domain of HIV-1 Tat and inhibit Tat- and P-TEFb-dependent transcription from the HIV-1 promoter. This transcriptional repression is cell-type specific and can operate via Tat and cyclin T1. Genomic and sequence comparisons indicate that the I-mf and HIC genes, as well as flanking genes, diverged from a duplicated chromosomal region. Our findings link I-mfa and HIC to viral replication, and suggest that P-TEFb is modulated in the Wnt signaling pathway.
Wang
Qi
Q
University of Medicine and Dentistry of New Jersey, Department of Biochemistry and Molecular Biology, New Jersey Medical School, Newark, NJ 07103-2714, USA.
Young
Tara M
TM
Mathews
Michael B
MB
Pe'ery
Tsafi
T
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D056906:Cyclin T; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D016213:Cyclins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D019143:Evolution, Molecular; D020440:Gene Duplication; D015696:Gene Products, tat / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D018006:Myogenic Regulatory Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D054322:tat Gene Products, Human Immunodeficiency Virus
C503684:CCNT1 protein, human; C441622:CCNT2 protein, human; D056906:Cyclin T; D016213:Cyclins; D017931:DNA Primers; D015696:Gene Products, tat; C478034:MDFIC protein, human; D046912:Multiprotein Complexes; D018006:Myogenic Regulatory Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; C101295:MDFI protein, human; D042925:Positive Transcriptional Elongation Factor B; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9