The Cell Cycle Control Element of Histone H4 Gene Transcription Is Maximally Responsive to Interferon Regulatory Factor Pairs IRF-1/IRF-3 and IRF-1/IRF-7

The mouse histone H4 gene, when stably transformed into L cells on the PSV2gpt shuttle vector, is cell cycle regulated in parallel with the endogenous H4 genes. This was determined in exponentially growing pools of transformants fractionated into cell cycle-specific stages by centrifugal elutriation, a method for purifying cells at each stage of the cell cycle without the use of treatments that arrest growth. Linker additions in the 5' noncoding region of the H4 RNA or in the coding region of the gene did not affect the cell cycle-regulated expression of the modified H4 gene even though the overall level of expression was altered. However, replacing the H4 promoter with the human alpha-2 globin promoter, so that the histone transcript produced by the chimeric gene remains essentially unchanged, resulted in the constitutive expression of H4 mRNA during all phases of the cell cycle with no net increase in H4 mRNA levels during the G1-to-S transition. From these results we conclude that all the information necessary for the cell cycle-regulated expression of the H4 gene is contained in the 5.2-kilobase subclone used in these studies with 228 nucleotides of 5'-flanking DNA and that the increase in H4 mRNA during the G1-to-S transition in the cell cycle is mediated by the H4 promoter and not by the increased stability of the H4 RNA.

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ATF1 and CREB Trans-Activate a Cell Cycle Regulated Histone H4 Gene at a Distal Nuclear Matrix Associated Promoter Element†

Biochemistry ◽

10.1021/bi971781s ◽

1997 ◽

Vol 36 (47) ◽

pp. 14447-14455 ◽

Cited By ~ 16

Author(s):

Bo Guo ◽

Janet L. Stein ◽

André J. van Wijnen ◽

Gary S. Stein

Keyword(s):

Cell Cycle ◽

Nuclear Matrix ◽

Promoter Element ◽

Histone H4 ◽

A Cell ◽

Histone H4 Gene

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Identification of HiNF-P, a Key Activator of Cell Cycle-Controlled Histone H4 Genes at the Onset of S Phase

Molecular and Cellular Biology ◽

10.1128/mcb.23.22.8110-8123.2003 ◽

2003 ◽

Vol 23 (22) ◽

pp. 8110-8123 ◽

Cited By ~ 42

Author(s):

Partha Mitra ◽

Rong-Lin Xie ◽

Ricardo Medina ◽

Hayk Hovhannisyan ◽

S. Kaleem Zaidi ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Cyclin E ◽

S Phase ◽

Phase Cell ◽

Regulatory Sequences ◽

Histone H4 ◽

Restriction Point ◽

Histone H4 Gene

ABSTRACT At the G1/S phase cell cycle transition, multiple histone genes are expressed to ensure that newly synthesized DNA is immediately packaged as chromatin. Here we have purified and functionally characterized the critical transcription factor HiNF-P, which is required for E2F-independent activation of the histone H4 multigene family. Using chromatin immunoprecipitation analysis and ligation-mediated PCR-assisted genomic sequencing, we show that HiNF-P interacts with conserved H4 cell cycle regulatory sequences in vivo. Antisense inhibition of HiNF-P reduces endogenous histone H4 gene expression. Furthermore, we find that HiNF-P utilizes NPAT/p220, a substrate of the cyclin E/cyclin-dependent kinase 2 (CDK2) kinase complex, as a key coactivator to enhance histone H4 gene transcription. The biological role of HiNF-P is reflected by impeded cell cycle progression into S phase upon antisense-mediated reduction of HiNF-P levels. Our results establish that HiNF-P is the ultimate link in a linear signaling pathway that is initiated with the growth factor-dependent induction of cyclin E/CDK2 kinase activity at the restriction point and culminates in the activation of histone H4 genes through HiNF-P at the G1/S phase transition.

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DNA topoisomerase II sites in the histone H4 gene during the highly synchronous cell cycle of Physarum polycephalum [published erratum appears in Nucleic Acids Res 1998 Oct 15;26(20):following 4789]

Nucleic Acids Research ◽

10.1093/nar/26.9.2042 ◽

1998 ◽

Vol 26 (9) ◽

pp. 2042-2049 ◽

Cited By ~ 5

Author(s):

V Borde

Keyword(s):

Cell Cycle ◽

Nucleic Acids ◽

Physarum Polycephalum ◽

Topoisomerase Ii ◽

Dna Topoisomerase Ii ◽

Histone H4 ◽

Dna Topoisomerase ◽

Synchronous Cell ◽

Histone H4 Gene

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Interferon Regulatory Factor 6 Promotes Cell Cycle Arrest and Is Regulated by the Proteasome in a Cell Cycle-Dependent Manner

Molecular and Cellular Biology ◽

10.1128/mcb.01866-07 ◽

2008 ◽

Vol 28 (7) ◽

pp. 2235-2243 ◽

Cited By ~ 53

Author(s):

Caleb M. Bailey ◽

Daniel E. Abbott ◽

Naira V. Margaryan ◽

Zhila Khalkhali-Ellis ◽

Mary J. C. Hendrix

Keyword(s):

Cell Cycle ◽

Epithelial Cells ◽

Cell Cycle Arrest ◽

Interferon Regulatory Factor ◽

Mammary Epithelial ◽

Dependent Manner ◽

Regulatory Factor ◽

Cycle Arrest ◽

Interferon Regulatory Factor 6 ◽

And Function

ABSTRACT Interferon regulatory factor 6 (IRF6) is a novel and unique member of the IRF family of transcription factors. IRF6 has not been linked to the regulatory pathways or functions associated with other IRF family members, and the regulation and function of IRF6 remain unknown. We recently identified a protein interaction between IRF6 and the tumor suppressor maspin. To gain insight into the biological significance of the maspin-IRF6 interaction, we examined the regulation and function of IRF6 in relation to maspin in normal mammary epithelial cells. Our results demonstrate that in quiescent cells, IRF6 exists primarily in a nonphosphorylated state. However, cellular proliferation leads to rapid IRF6 phosphorylation, resulting in proteasome-dependent IRF6 degradation. These data are supported in situ by the increased expression of IRF6 in quiescent, differentiated lobuloalveolar cells of the lactating mammary gland compared to its expression in proliferating ductal and glandular epithelial cells during pregnancy. Furthermore, the reexpression of IRF6 in breast cancer cells results in cell cycle arrest, and the presence of maspin augments this response. These data support a model in which IRF6, in collaboration with maspin, promotes mammary epithelial cell differentiation by facilitating entry into the G0 phase of the cell cycle.

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