Biochemical and functional analysis of highly phosphorylated forms of c‐Jun protein

Ui, Michio; Sonobe, M.; Ito, Tsuyohito; Murakami, Masao; Okazaki, Satoshi; Takada, Misato; Sato, Toshitaka; Iba, Hideo

doi:10.1016/s0014-5793(98)00618-8

Cited by 15 publications

(11 citation statements)

References 24 publications

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“…relative phosphorylation status, visualized by the retarded mobility, is the result of phosphorylation at serines 63 and 73 and threonines 91 and 93 (30). To more directly compare the c-Jun mobility profiles, we plotted the film density profile against migration distance in the gel, normalizing to the peak intensity for each trace.…”

Section: The C-jun Stress Response Is Strongly Suppressed In Jnk2mentioning

confidence: 99%

All JNKs Can Kill, but Nuclear Localization Is Critical for Neuronal Death

Björkblom

Vainio

Hongisto

et al. 2008

Journal of Biological Chemistry

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JNKs are implicated in a range of brain pathologies and receive considerable attention as potential therapeutic targets. However, JNKs also regulate physiological and homeostatic processes. An attractive hypothesis from the drug development perspective is that distinct JNK isoforms mediate "physiological" and "pathological" responses. However, this lacks experimental evaluation. Here we investigate the isoforms, subcellular pools, and c-Jun/ATF2 targets of JNK in death of central nervous system neurons following withdrawal of trophic support. We use gene knockouts, gene silencing, subcellularly targeted dominant negative constructs, and pharmacological inhibitors. Combined small interfering RNA knockdown of all JNKs 1, 2, and 3, provides substantial neuroprotection. In contrast, knockdown or knock-out of individual JNKs or two JNKs together does not protect. This explains why the evidence for JNK in neuronal death has to date been largely pharmacological. Complete knockdown of c-Jun and ATF2 using small interfering RNA also fails to protect, casting doubt on c-Jun as a critical effector of JNK in neuronal death. Nonetheless, the death requires nuclear but not cytosolic JNK activity as nuclear dominant negative inhibitors of JNK protect, whereas cytosolic inhibitors only block physiological JNK function. Thus any one of the three JNKs is capable of mediating apoptosis and inhibition of nuclear JNK is protective.

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Section: The C-jun Stress Response Is Strongly Suppressed In Jnk2mentioning

confidence: 99%

All JNKs Can Kill, but Nuclear Localization Is Critical for Neuronal Death

Björkblom

Vainio

Hongisto

et al. 2008

Journal of Biological Chemistry

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“…However, part of this di erence between c-Jun and v-Jun in their dependence on JNK is attributable to the cell system. c-Jun transforms avian cells as a single oncoprotein, and that transformation also does not require Nterminal phosphorylation; mutation of the JNK phosphorylation sites does not a ect the transforming ability of c-Jun for avian cells (Metivier et al, 1993;Ui et al, 1998).…”

Section: Transactivation: the Importance Of Deltamentioning

confidence: 99%

Jun, the oncoprotein

2001

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We give a self-contained introduction to isolated points on curves and their counterpoint, parameterized points, that situates these concepts within the study of the arithmetic of curves. In particular, we show how natural geometric constructions of infinitely many degree d points on curves motivate the definitions of P 1 -and AV-parameterized points and explain how a result of Faltings implies that there are only finitely many isolated points on any curve. We use parameterized points to deduce properties of the density degree set and review how the minimum density degree relates to the gonality. The paper includes several examples that illustrate the possible behaviors of degree d points.

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“…) that are phosphorylated by the c-Jun N-terminal kinase/stress-activated protein kinase (47). The second mutant, c-Jun A265D In265, contains a substitution of alanine to aspartic acid at position 265 as well as an insertion of three negatively charged amino acids after residue 265.…”

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confidence: 99%

c-Jun Transactivates the Promoter of the Human p21 Gene by Acting as a Superactivator of the Ubiquitous Transcription Factor Sp1

Kardassis

Papakosta

Pardali

et al. 1999

Journal of Biological Chemistry

183

149

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The cell cycle inhibitor protein p21 WAF1/Cip1 (p21) is a critical downstream effector in p53-dependent mechanisms of growth control and p53-independent pathways of terminal differentiation. We have recently reported that the transforming growth factor-␤ pathway-specific Smad3 and Smad4 proteins transactivate the human p21 promoter via a short proximal region, which contains multiple binding sites for the ubiquitous transcription factor Sp1. In the present study we show that the Sp1-occupied promoter region mediates transactivation of the p21 promoter by c-Jun and the related proteins JunB, JunD, and ATF-2. By using gel electrophoretic mobility shift assays we show that this region does not contain a binding site for c-Jun. In accordance with the DNA binding data, c-Jun was unable to transactivate the p21 promoter when overexpressed in the Sp1-deficient p21WAF1/Cip1 (p21) modulates cyclin-dependent kinase activity resulting in cell growth arrest or progression (1, 2). In addition p21 prevents DNA synthesis and regulates DNA methylation by directly interacting with proliferating cell nuclear antigen, a subunit of DNA polymerase ␦ (1, 3). Finally, p21 plays important roles in the control of cell senescence, apoptosis, and differentiation (4 -6).p21 gene expression is regulated by a long list of inducers under physiological or pathological conditions. These include the following: (a) tumor suppressors such as p53 (7); (b) factors that control differentiation of diverse cell types such as hematopoietic cells by phorbol esters and steroid superfamily members (8, 9), muscle and skin cells during terminal differentiation (10, 11), hepatocytes during normal liver organogenesis or liver regeneration (12, 13), and nerve cells by nerve growth factor (14, 15); and (c) growth factors, cytokines, hormones, and stress factors such as serum and platelet-derived growth factor (16), tumor necrosis factor ␣ (17), phorbol esters or phosphatase inhibitors (18), interferon ␥ (19), progesterone (20), and transforming growth factor-␤ (TGF-␤) 1 or activin A (21-23) and their signaling effectors, Smad proteins (24, 25).Of particular importance has been the elucidation of the transcriptional mechanisms that operate during p21 gene induction by the above listed factors. For many such factors, including p53, retinoic acid, vitamin D 3 , interferon ␥, and others, specific cis-acting DNA motifs have been identified on the p21 promoter in a region that extends between positions Ϫ2,300 and Ϫ210 relative to the transcriptional initiation site (9,19,26). On the other hand, an increasing number of regulatory factors including TGF-␤, progesterone, phorbol esters, and phosphatase inhibitors mediate their effects on p21 gene expression via the proximal region of the promoter (Ϫ210 to ϩ1 base pairs) (10,14,18,20,21,23,25). The proximal promoter contains characteristic GC-rich motifs that serve as binding sites for members of the Sp1 family of ubiquitous transcription factors (21).Sp1 belongs to a zinc finger family of transcription factors that recog...

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Biochemical and functional analysis of highly phosphorylated forms of c‐Jun protein

Cited by 15 publications

References 24 publications

All JNKs Can Kill, but Nuclear Localization Is Critical for Neuronal Death

All JNKs Can Kill, but Nuclear Localization Is Critical for Neuronal Death

Jun, the oncoprotein

c-Jun Transactivates the Promoter of the Human p21 Gene by Acting as a Superactivator of the Ubiquitous Transcription Factor Sp1

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