ATF4 Is a Substrate of RSK2 and an Essential Regulator of Osteoblast Biology

Yang, Xiangli; Matsuda, Koichi; Bialek, Peter; Jacquot, Sylvie; Masuoka, Howard C.; Schinke, Thorsten; Li, Lingzhen; Brancorsini, Stefano; Sassone–Corsi, Paolo; Townes, Tim M.; Hanauer, André; Karsenty, Gérard

doi:10.1016/s0092-8674(04)00344-7

Cited by 757 publications

(806 citation statements)

References 42 publications

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“…For instance, Runx2 and Osx have been found to regulate osteoblast function in adult bone in addition to their primarily established role in osteoblastogenesis [23,24]. Another transcription factor, Atf4 regulates bone matrix deposition by mature osteoblasts [25]. Furthermore, several signaling pathways have been shown to regulate postnatal osteoblast function including Ihh [26], Wnt/Lrp5 [27], TGFb-BMP/Smads [28][29][30], BMP/MEKK2/MEK5-7/Jnk [31], b-adrenergic [32], IGF-1 [16], insulin [33] and PTH signaling [34].…”

Section: Discussionmentioning

confidence: 99%

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

Thouverey

Caverzasio

2012

Cell. Mol. Life Sci.

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Bone continuously remodels throughout life by coordinated actions of osteoclasts and osteoblasts. Abnormalities in either osteoclast or osteoblast functions lead to bone disorders. The p38 MAPK pathway has been shown to be essential in controlling osteoblast differentiation and skeletogenesis. Although p38a is the most abundant p38 member in osteoblasts, its specific individual contribution in regulating postnatal osteoblast activity and bone metabolism is unknown. To elucidate the specific role of p38a in regulating osteoblast function and bone homeostasis, we generated mice lacking p38a in differentiated osteoblasts. Osteoblast-specific p38a knockout mice were of normal weight and size. Despite non-significant bone alterations until 5 weeks of age, mutant mice demonstrated significant and progressive decrease in bone mineral density from that age. Adult mice deficient in p38a in osteoblasts displayed a striking reduction in cancellous bone volume at both axial and appendicular skeletal sites. At 6 months of age, trabecular bone volume was reduced by 62 % in those mice. Mutant mice also exhibited progressive decrease in cortical thickness of long bones. These abnormalities correlated with decreased endocortical and trabecular bone formation rate and reduced expressions of type 1 collagen, alkaline phosphatase, osteopontin and osteocalcin whereas bone resorption and osteoclasts remained unaffected. Finally, osteoblasts lacking p38a showed impaired marker gene expressions and defective mineralization in vitro. These findings indicate that p38a is an essential positive regulator of osteoblast function and postnatal bone formation in vivo.

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Section: Discussionmentioning

confidence: 99%

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

Thouverey

Caverzasio

2012

Cell. Mol. Life Sci.

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“…Phosphorylation of the a subunit of translation initiation factor (eIF2a) promotes translation of ATF4 and ATF4 phosphorylated by RSK2 increases transactivation ability (Yang et al, 2004). We initially examined the cellular expression levels of eIF2a kinase PERK, which was activated by endoplasmic reticulum stress, in cisplatin-resistant cells.…”

Section: Discussionmentioning

confidence: 99%

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

et al. 2007

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The mechanisms underlying cellular drug resistance have been extensively studied, but little is known about its regulation. We have previously reported that activating transcription factor 4 (ATF4) is upregulated in cisplatinresistant cells and plays a role in cisplatin resistance. Here, we find out a novel relationship between the circadian transcription factor Clock and drug resistance. Clock drives the periodical expression of many genes that regulate hormone release, cell division, sleep-awake cycle and tumor growth. We demonstrate that ATF4 is a direct target of Clock, and that Clock is overexpressed in cisplatin-resistant cells. Furthermore, Clock expression significantly correlates with cisplatin sensitivity, and that the downregulation of either Clock or ATF4 confers sensitivity of A549 cells to cisplatin and etoposide. Notably, ATF4-overexpressing cells show multidrug resistance and marked elevation of intracellular glutathione. The microarray study reveals that genes for glutathione metabolism are generally downregulated by the knockdown of ATF4 expression. These results suggest that the Clock and ATF4 transcription system might play an important role in multidrug resistance through glutathione-dependent redox system, and also indicate that physiological potentials of Clock-controlled redox system might be important to better understand the oxidative stress-associated disorders including cancer and systemic chronotherapy.

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“…ATF-4 has important effects on osteoblast function and atf4 null mice exhibit decreased osteoblastic activity, whereas forced ATF-4 expression induces osteoblastic gene markers [22,46]. CHOP interactions with Fos and Jun or ATF-4 might occur in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…CHOP expression also is induced by the pancreatic endoplasmic reticulum kinase (PERK), an effect mediated by an increase in atf-4 translation [15,20]. Perk null mice and humans with perk gene mutations develop osteopenia due to increased osteoblast sensitivity to cellular stress, and atf4 null mice exhibit decreased bone formation due to impaired osteoblastic function [21,22]. Similarly, chop null mice exhibit decreased bone formation, indicating that CHOP plays a role in osteoblastic function in vivo [23].…”

Section: Introductionmentioning

confidence: 99%

CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia

Pereira

Stadmeyer

Smith

et al. 2007

Bone

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CCAAT enhancer binding protein (C/EBP) homologous protein (CHOP), is a member of the C/EBP family of nuclear proteins and plays a role in osteoblastic and adipocytic cell differentiation. CHOP is necessary for normal bone formation, but the consequences of its overexpression in vivo are not known. To investigate the direct actions of CHOP on bone remodeling in vivo, we generated transgenic mice overexpressing CHOP under the control of the human osteocalcin promoter. CHOP transgenics exhibited normal weight and reduced bone mineral density. Static and dynamic femoral bone histomorphometry revealed that CHOP overexpression caused reduced trabecular bone volume, secondary to decreased bone formation rates. One of 2 lines displayed a decrease in the number of osteoblasts, but in vivo bromodeoxyuridine labeling demonstrated that CHOP overexpression did not have an effect on osteoblastic cell replication. The decreased osteoblast cell number was accounted by an increase in apoptosis, as determined by DNA fragmentation measured by transferase-mediated digoxigenin-deoxyuridine triphosphate (dUTP) in situ nick-end labeling (TUNEL) reaction. In conclusion, transgenic mice overexpressing CHOP in the bone microenvironment have impaired osteoblastic function leading to osteopenia.

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ATF4 Is a Substrate of RSK2 and an Essential Regulator of Osteoblast Biology

Cited by 757 publications

References 42 publications

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia

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