Cyclin T2 Is Essential for Mouse Embryogenesis

Abstract

The positive transcription elongation factor b (P-TEFb) is essential for the elongation of transcription and cotranscriptional processing by RNA polymerase II. In mammals, it contains predominantly the C-type cyclin cyclin T1 (CycT1) or CycT2 and cyclin-dependent kinase 9 (Cdk9). To determine if these cyclins have redundant functions or affect distinct sets of genes, we genetically inactivated the CycT2 gene (Ccnt2) using the ␤-galactosidase-neomycin gene (␤-geo) gene trap technology in the mouse. Visualizing ␤-galactosidase during mouse embryogenesis revealed that CycT2 is expressed abundantly during embryogenesis and throughout the organism in the adult. This finding was reflected in the expression of CycT2 in all adult tissues and organs. However, despite numerous matings of heterozygous mice, we observed no CycT2 ؊/؊ embryos, pups, or adult mice. This early lethality could have resulted from decreased expression of critical genes, which were revealed by short interfering RNAs against CycT2 in embryonic stem cells. Thus, CycT1 and CycT2 are not redundant, and these different P-TEFb complexes regulate subsets of distinct genes that are important for embryonic development.Eukaryotic transcription by RNA polymerase II (RNAPII) is regulated at several distinct steps, which include initiation, promoter clearance, elongation, and cotranscriptional processing of primary transcripts (19,25,27). Of these, elongation is regulated by the positive transcription elongation factor b (PTEFb), which contains predominantly the C-type cyclin cyclin T1 (CycT1) or CycT2 and cyclin-dependent kinase 9 (Cdk9). All these different P-TEFb complexes phosphorylate serines at position 2 (S2) in the C-terminal domain (CTD) of RNAPII, as well as components of the negative transcription elongation factor, which contains minimally the DRB (5,6-dichloro-1-␤- D-ribofuranosylbenzimidazole) sensitivity-inducing factor (DSIF) and the negative elongation factor. These posttranslational modifications exchange basal transcription factors for splicing and polyadenylation machineries on RNAPII, as well as modify DSIF for productive elongation (25).Although these P-TEFb complexes can phosphorylate the CTD and lead to transcriptional elongation when recruited to RNAPII via heterologous nucleic acid-tethering systems, it is not clear whether they have redundant or unique functions in cells (18,33). Thus far, CycT1, which is the most abundant of these cyclins, has been implicated as the coactivator of the transcriptional transactivator Tat from human immunodeficiency virus, RelA from NF-B, class II transactivator, the protooncogene c-myc, several members of the steroid hormone receptor family, and the autoimmune regulator AIRE (3, 8, 14-16, 24, 29, 36). Moreover, Runx1, which is the active repressor of CD4 expression in double-negative thymocytes, decoys CycT1 away from the CD4 promoter, thus keeping the

MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia

“…33 In mammals, P-TEFb is essential for the elongation of transcription and cotranscriptional processing by RNA polymerase II, and different P-TEFb complexes can regulate subsets of distinct genes that are important for embryonic development. 34 We observed inhibition of proliferation in THP-1 cells and a decreased level of phosphorylated Rb by siRNA-mediated knockdown of CCNT2, which is consistent with previous findings. 27 We miR-29a AND miR-142-3p AND MYELOID DIFFERENTIATION 4999 BLOOD, 24 MAY 2012 ⅐ VOLUME 119, NUMBER 21…”

The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes

“…This implies that CycK/Cdk12 and/ or CycK/Cdk13 kinases play a major role during embryo development, perhaps by the modulation of phosphorylation of the CTD of RNAPII during expression of the genes regulating the development. Similarly, genetic inactivation of CycT2 led to embryonic lethality during the preimplantation period (Kohoutek et al 2009). These results emphasize the importance of CTD kinases for the regulation of early stages of development.…”

Downregulation of microRNA‑142‑3p and its tumor suppressor role in gastric cancer

“…CCNT2 is a component of the P-TEFb complex, which is essential for transcription initiation and elongation that is mediated by RNA polymerase II. P-TEFb complexes have critical roles in embryonic development and multiple cellular processes (35,36). The role of CCNT2 in regulating cell growth and tumorigenesis are not clear, with the exception of one study which reported that CCNT2 was able to increase the proliferation of THP-1 cells and inhibit monocytic differentiation (22).…”