RNA Polymerase III Transcription: Its Control by Tumor Suppressors and Its Deregulation by Transforming Agents

Brown, T.R.P.; Scott, Pamela Sharkey; Stein, Torsten; Winter, Andrew G.; White, Robert J.

doi:10.3727/000000001783992713

Cited by 36 publications

(23 citation statements)

References 137 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most transformed cell lines and tumors have abnormally high levels of PolIII activity (5). Various mechanisms may contribute to this deregulation, but probably the most frequent is the loss of repression by the tumor suppressor RB, which binds TFIIIB and blocks its interactions with TFIIIC2 and PolIII (55).…”

Section: Discussionmentioning

confidence: 99%

“…Various mechanisms may contribute to this deregulation, but probably the most frequent is the loss of repression by the tumor suppressor RB, which binds TFIIIB and blocks its interactions with TFIIIC2 and PolIII (55). This function is compromised by mutations which arise naturally in cancers (5,55,64), by the binding of viral oncoproteins (28,64), and by RB hyperphosphorylation due to overexpression of cyclin D1 or loss of p16 (47). The discovery that mammalian CK2 activates PolIII transcription suggests another potential mechanism that contributes to the overexpression of class III genes in certain types of malignancy.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

CK2 Forms a Stable Complex with TFIIIB and Activates RNA Polymerase III Transcription in Human Cells

Johnston

Allison

Morton

et al. 2002

Molecular and Cellular Biology

View full text Add to dashboard Cite

CK2 is a highly conserved protein kinase with growth-promoting and oncogenic properties. It is known to activate RNA polymerase III (PolIII) transcription in Saccharomyces cerevisiae and is shown here to also exert a potent effect on PolIII in mammalian cells. Peptide and chemical inhibitors of CK2 block PolIII transcription in human cell extracts. Furthermore, PolIII transcription in mammalian fibroblasts is decreased significantly when CK2 activity is compromised by chemical inhibitors, antisense oligonucleotides, or kinase-inactive mutants. Coimmunoprecipitation and cofractionation show that endogenous human CK2 associates stably and specifically with the TATA-binding protein-containing factor TFIIIB, which brings PolIII to the initiation site of all class III genes. Serum stimulates TFIIIB phosphorylation in vivo, an effect that is diminished by inhibitors of CK2. Binding to TFIIIC2 recruits TFIIIB to most PolIII promoters; this interaction is compromised specifically by CK2 inhibitors. The data suggest that CK2 stimulates PolIII transcription by binding and phosphorylating TFIIIB and facilitating its recruitment by TFIIIC2. CK2 also activates PolI transcription in mammals and may therefore provide a mechanism to coregulate the output of PolI and PolIII. CK2 provides a rare example of an endogenous activity that operates on the PolIII system in both mammals and yeasts. Such evolutionary conservation suggests that this control may be of fundamental importance.Protein kinase CK2 (formerly known as casein kinase II) is ubiquitous and highly conserved in eukaryotes (reviewed in references 1 and 29). It phosphorylates proteins on serine and threonine in both the nucleus and the cytoplasm. CK2 exists as a tetramer, composed of two isozymic catalytic subunits, ␣ and ␣Ј, and two copies of a regulatory ␤ subunit or one copy each of ␤ and the closely related ␤Ј. The CK2␣ and CK2␣Ј subunits are nearly 90% identical and can compensate for each other, but there is also some functional specialization (57, 69). The ␤ subunits allow optimal kinase activity and can regulate substrate specificity; they form a stable dimer linking the two catalytic subunits, which do not contact each other (35).Although its signaling function has long remained obscure, CK2 has been shown recently to form part of the Wnt pathway in both Drosophila and mammals (54, 65). Many studies have found that increases in the level and/or activity of CK2 are associated with cell growth and proliferation (for example, references 3, 4, 7, 25, 30, 34, and 39). Thus, CK2 expression can be increased by mitogens (7, 39), and CK2 is most abundant in cells with high mitotic activity, such as transformed cells and normal colorectal mucosa (34). Indeed, microinjection of CK2 can induce immediate-early gene expression in the absence of growth factors (11). Conversely, inactivation of CK2 by specific antibodies or antisense oligonucleotides can arrest the proliferation of primary human fibroblasts (41,42). Similarly, cell cycle progression is blocked in Saccharomyces ...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CK2 Forms a Stable Complex with TFIIIB and Activates RNA Polymerase III Transcription in Human Cells

Johnston

Allison

Morton

et al. 2002

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…This region is necessary and sufficient for RB to bind TFIIIB and repress pol III transcription (White et al, 1996;Chu et al, 1997;Larminie et al, 1997). Accordingly, this function is ablated by substitutions or small deletions in the pocket that arose naturally in tumours (White et al, 1996;Brown et al, 2000;Felton-Edkins et al, 2003b). (Figure 2).…”

Section: Derepression Of Tfiiibmentioning

confidence: 99%

RNA polymerase III transcription and cancer

2004

View full text Add to dashboard Cite

RNA polymerase (pol) III synthesizes a range of essential products, including tRNA, 5S rRNA and 7SL RNA, which are required for protein synthesis and trafficking. High rates of pol III transcription are necessary for cells to sustain growth. A wide range of transformed and tumour cell types have been shown to express elevated levels of pol III products. This review will summarize what is known about the mechanisms responsible for this deregulation. Some transforming agents have been shown to stimulate expression of the pol III-specific transcription factors TFIIIB or TFIIIC2. In addition, TFIIIB is bound and activated by several oncogenic proteins, including cMyc. Conversely, TFIIIB interacts in healthy cells with the tumour suppressors RB and p53. Indeed, the ability to limit pol III transcription through TFIIIB may contribute to their growth-suppression capacities. The function of p53 and/or RB is compromised in most if not all transformed cells; the resultant derepression of TFIIIB may provide an almost universal route to deregulate pol III transcription in cancers. In addition to effects on protein synthesis and growth, there is a precedent for a pol III product having oncogenic activity.

show abstract

“…The embryos were washed 5 times with 0.1ϫ OR2 buffer and then placed at 18°C. GVs were isolated from oocytes that were initially swelled by incubation in TM buffer ( 7.5]-100 mM NaCl-0.1% NP-40-5 mM DTT) at 4°C for 2 h. Beads were washed five times with 1 ml of the same buffer before resuspension in loading buffer containing sodium dodecyl sulfate (SDS). The immunoprecipitated samples were analyzed by SDS-polyacrylamide gel electrophoresis, followed by autoradiography.…”

Section: Methodsmentioning

confidence: 99%

Restricted Specificity of Xenopus TFIIIA for Transcription of Somatic 5S rRNA Genes

Ghose

Malik

Huber

2004

Molecular and Cellular Biology

View full text Add to dashboard Cite

Xenopus transcription factor IIIA (TFIIIA) is phosphorylated on serine-16 by CK2. Replacements with alanine or glutamic acid were made at this position in order to address the question of whether phosphorylation possibly influences the function of this factor. Neither substitution has an effect on the DNA or RNA binding activity of TFIIIA. The wild-type factor and the alanine variant activate transcription of somatic-and oocyte-type 5S rRNA genes in nuclear extract immunodepleted of endogenous TFIIIA. The glutamic acid variant (S16E) supports the transcription of somatic-type genes at levels comparable to those of wild-type TFIIIA; however, there is no transcription of the oocyte-type genes. This differential behavior of the phosphomimetic mutant protein is also observed in vivo when using early-stage embryos, where this mutant failed to activate transcription of the endogenous oocyte-type genes. Template exclusion assays establish that the S16E mutant binds to the oocyte-type 5S rRNA genes and recruits at least one other polymerase III transcription factor into an inactive complex. Phosphorylation of TFIIIA by CK2 may allow the factor to continue to act as a positive activator of the somatic-type genes and simultaneously as a repressor of the oocyte-type 5S rRNA genes, indicating that there is a mechanism that actively promotes repression of the oocyte-type genes at the end of oogenesis.The synthesis of 5S rRNA during Xenopus oogenesis and embryogenesis provides a paradigm for developmental control of transcription (79). The oocyte-type 5S rRNA genes, which number more than 20,000 per haploid genome, are transcribed during oogenesis and briefly during early embryogenesis. The 400 somatic-type genes are active at all stages of development. Formation of transcription initiation complexes on the internal promoters of the 5S rRNA genes requires the initial binding of transcription factor IIIA (TFIIIA), followed by the ordered addition of TFIIIC and TFIIIB (46). Despite minor differences in the sequences of the two types of 5S rRNA genes, TFIIIA binds to the internal promoters of both with equal affinity (52). TFIIIC, however, preferentially binds to and stabilizes the complex of TFIIIA on the somatic-type genes (44, 79). Thus, the differential transcription of the two 5S rRNA genes during early development could, at least in part, be due to the levels of transcription factors. Nonetheless, the principal mediator of 5S rRNA gene transcription from gastrulation onward is chromatin structure.Histone H1 orchestrates the repression of oocyte-type genes in somatic cells (5,21,66,78). This inhibition occurs after the midblastula transition (MBT), when adult H1A begins to replace the maternal histone H1 variant, H1M (20,21,40). Nucleosomes are arranged differently over the two types of 5S RNA genes in somatic cells (10, 30, 83) because histone H1 acts as an architectural determinant (58, 67). In the presence of the linker histone, a stable nucleosome is positioned on the oocyte 5S rRNA gene that prevents binding of TFIIIA,...

show abstract

RNA Polymerase III Transcription: Its Control by Tumor Suppressors and Its Deregulation by Transforming Agents

Cited by 36 publications

References 137 publications

CK2 Forms a Stable Complex with TFIIIB and Activates RNA Polymerase III Transcription in Human Cells

CK2 Forms a Stable Complex with TFIIIB and Activates RNA Polymerase III Transcription in Human Cells

RNA polymerase III transcription and cancer

Restricted Specificity of Xenopus TFIIIA for Transcription of Somatic 5S rRNA Genes

Contact Info

Product

Resources

About