Multisite phosphorylation provides sophisticated regulation of transcription factors

Holmberg, Carina I.; Tran, Stefanie E.F.; Eriksson, John E.; Sistonen, Lea

doi:10.1016/s0968-0004(02)02207-7

Cited by 289 publications

(240 citation statements)

References 58 publications

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“…In the nucleus, Hsf1 binds to heat shock element (HSE) sequences present in the promoter regions of Hsps (Amin et al 1988). In addition, regulation of Hsf1-mediated transcriptional activity is mediated by both constitutive and stress-inducible phosphorylation (Kline and Morimoto 1997;Holmberg et al 2001Holmberg et al , 2002Guettouche et al 2005). Hsf1 −/− mice are viable but exhibit some degree of prenatal lethality and postnatal growth retardation (Xiao et al 1999).…”

Section: Figmentioning

confidence: 99%

Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock

Taleb

Brandon

Lee

et al. 2008

JARO

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Sensory hair cells of the inner ear are sensitive to death from aging, noise trauma, and ototoxic drugs. Ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Exposure to aminoglycosides results in hair cell death that is mediated by specific apoptotic proteins, including cJun N-terminal kinase (JNK) and caspases. Induction of heat shock proteins (Hsps) is a highly conserved stress response that can inhibit JNK-and caspasedependent apoptosis in a variety of systems. We have previously shown that heat shock results in a robust upregulation of Hsps in the hair cells of the adult mouse utricle in vitro. In addition, heat shock results in significant inhibition of both cisplatin-and aminoglycoside-induced hair cell death. In our system, Hsp70 is the most strongly induced Hsp, which is upregulated over 250-fold at the level of mRNA 2 h after heat shock. Therefore, we have begun to examine the role of Hsp70 in mediating the protective effect of heat shock. To determine whether Hsp70 is necessary for the protective effect of heat shock against aminoglycoside-induced hair cell death, we utilized utricles from Hsp70.1/3 −/− mice. While heat shock inhibited gentamicin-induced hair cell death in wild-type utricles, utricles from Hsp70.1/3 −/− mice were not protected. In addition, we have examined the role of the major heat shock transcription factor, Hsf1, in mediating the protective effect of heat shock. Utricles from Hsf1 −/− mice and wild-type littermates were exposed to heat shock followed by gentamicin. The protective effect of heat shock on aminoglycoside-induced hair cell death was only observed in wildtype mice and not in Hsf1 −/− mice. To determine whether Hsp70 is sufficient to protect hair cells, we have utilized transgenic mice that constitutively overexpress Hsp70. Utricles from Hsp70-overexpressing mice and wild-type littermates were cultured in the presence of varying neomycin concentrations for 24 h. The Hsp70-overexpressing utricles were significantly protected against neomycin-induced hair cell death at moderate to high doses of neomycin. This protective effect was achieved without a heat shock. Taken together, these data indicate that Hsp70 and Hsf1 are each necessary for the protective effect of heat shock against aminoglycoside-induced death. Furthermore, overexpression of Hsp70 alone significantly inhibits aminoglycoside-induced hair cell death.

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Section: Figmentioning

confidence: 99%

Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock

Taleb

Brandon

Lee

et al. 2008

JARO

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“…Phosphorylation within transcriptional regulatory domains is well known to regulate the assembly of transcription factor complexes (Whitmarsh and Davis, 2000;Holmberg et al, 2002). Q-rich transcriptional regulatory domains have been described for several nuclear factors including AP-2, GAGA factor, the Sp-family of transcription factors, CREB/CREM and transcriptional coactivators such as p300 and the SRC family (Kraus et al, 1999;Wilkins and Lis, 1999;Leo and Chen, 2000;Servillo et al, 2002;Li et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

DNA-PK phosphorylation sites on Oct-1 promote cell survival following DNA damage

et al. 2007

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“…There are several mechanisms responsible for regulating their numbers in cells, which act at various stages of protein production [1-4], activation [5], and degradation. A recent study has provided genome-wide information on protein numbers in Escherichia coli along with their cell-to-cell variability [6].…”

Section: Introductionmentioning

confidence: 99%

Effects of multimerization on the temporal variability of protein complex abundance

et al. 2013

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We explore whether the process of multimerization can be used as a means to regulate noise in the abundance of functional protein complexes. Additionally, we analyze how this process affects the mean level of these functional units, response time of a gene, and temporal correlation between the numbers of expressed proteins and of the functional multimers. We show that, although multimerization increases noise by reducing the mean number of functional complexes it can reduce noise in comparison with a monomer, when abundance of the functional proteins are comparable. Alternatively, reduction in noise occurs if both monomeric and multimeric forms of the protein are functional. Moreover, we find that multimerization either increases the response time to external signals or decreases the correlation between number of functional complexes and protein production kinetics. Finally, we show that the results are in agreement with recent genome-wide assessments of cell-to-cell variability in protein numbers and of multimerization in essential and non-essential genes in Escherichia coli, and that the effects of multimerization are tangible at the level of genetic circuits.

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Multisite phosphorylation provides sophisticated regulation of transcription factors

Cited by 289 publications

References 58 publications

Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock

Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock

DNA-PK phosphorylation sites on Oct-1 promote cell survival following DNA damage

Effects of multimerization on the temporal variability of protein complex abundance

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