Granulin epithelin precursor: a bone morphogenic protein 2‐inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis

Feng, Jian Q.; Guo, Fengjin; Jiang, Baichun; Zhang, Yan; Frenkel, Sally R.; Wang, Dawei; Tang, Wei; Xie, Yixia; Liu, Chuanju

doi:10.1096/fj.09-144659

Cited by 112 publications

(168 citation statements)

References 70 publications

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“…Based on the findings in this study, together with the literature (Ron and Walter, 2007;Murakami et al, 2009;Han et al, 2014;Cantu' et al, 2011;Roca et al, 2005;Kronenberg, 2006;Yamamoto et al, 2004), as well as our previous reports (Guo et al, 2014b;Han et al,2014;Feng et al, 2010), we propose a model for illustrating the role and regulation of ATF6a in the course of hypertrophic chondrocyte differentiation (Fig. 8I).…”

Section: There Are Three Runx2-binding Consensus Sequences [Rccrc(a/tsupporting

confidence: 82%

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ATF6a, a Runx2-activable transcription factor, is a novel regulator of chondrocyte hypertrophy

Guo

Han

et al. 2015

Journal of Cell Science

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Our previous research has shown that the spliced isoform of XBP1 (XBP1s) is an important downstream mediator of BMP2 and is involved in BMP2-stimulated chondrocyte differentiation. Herein, we report that ATF6 and its cleaved N-terminal cytoplasmic domain (known as ATF6a) are expressed in growth plate chondrocytes. We find that these proteins are differentially induced during BMP2-triggered chondrocyte differentiation. This differential expression probably results from the activation of the ATF6 gene by Runx2 and its repression by the Sox6 transcription factor. Runx2 and Sox6 act through their respective binding elements on the ATF6 gene. When overexpressed, ATF6 and ATF6a intensify chondrogenesis; our studies demonstrate that under the stimulation of ATF6 and ATF6a, chondrocytes tend to be hypertrophied and mineralized, a process leading to bone formation. By contrast, lowering expression of ATF6a by use of its specific siRNA suppresses chondrocyte differentiation. Moreover, ATF6a interacts with Runx2 and augments the Runx2-mediated hypertrophication of chondrocytes. Importantly, overexpression and knockdown of ATF6a during the chondrocyte hypertrophy process also led to altered expressions of IHH and PTHrP (also known as PTHLH). Taken together, these findings indicate that ATF6a favorably controls chondrogenesis and bone formation (1) by acting as a co-factor of Runx2 and enhancing Runx2-incited hypertrophic chondrocyte differentiation, and (2) by affecting IHH and PTHrP signaling.

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Section: There Are Three Runx2-binding Consensus Sequences [Rccrc(a/tsupporting

confidence: 82%

“…5. For Safranin O and Fast Green staining, and Alizarin Red or Alcian Blue staining, the methods were as explained previously (Feng et al, 2010;Guo et al, 2014a,b).…”

Section: Fetal Mouse Bone Explants Culturementioning

confidence: 99%

ATF6a, a Runx2-activable transcription factor, is a novel regulator of chondrocyte hypertrophy

Guo

Han

et al. 2015

Journal of Cell Science

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“…PGRN is a 66-68 kDa secreted glycoprotein, also known as proepithelin cell-derived growth factor (PCDGF), has been shown to be a pluripotent growth factor that plays a role in cell-cycle progression, angiogenesis, wound healing, cancers, and neurodegenerative diseases (He and Bateman, 2003;Feng et al, 2010).…”

Section: Progranulin (Pgrn)mentioning

confidence: 99%

Adipose Tissue as an Endocrine Organ: An Update on Pro-inflammatory and Anti-inflammatory Microenvironment

2015

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Adipose tissue is recognized as an active endocrine organ that produces a number of endocrine substances referred to as "adipokines" including leptin, adiponectin, adipolin, visfatin, omentin, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), resistin, pigment epithelium-derived factor (PEDF), and progranulin (PGRN) which play an important role in the food intake regulation and significantly influence insulin sensitivity and in some cases directly affect insulin resistance in skeletal muscle, liver, and adipose tissue. The review summarizes current knowledge about adipose tissue-derived hormones and their influence on energy homeostasis regulation. The possible therapeutic potential of these adipokines in the treatment of insulin resistance, endothelial dysfunction, a pro-inflammatory response, obesity, eating disorders, progression of atherosclerosis, type 1 diabetes, and type 2 diabetes is discussed.

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“…However, previous evidences suggested that endoplasmic reticulum (ER) stress may be involved in PGRN action in some other pathological processes. For instance, PGRN activates ERK1/2 signaling pathway, 16 whereas XBP1S, a key transcription factor in ER stress, inhibits ER stress-mediated apoptosis through the Erk1/2 signaling pathway. 17 In addition, tumor necrosis factor-a (TNFa), a putative inducer of inflammation, ER stress and insulin resistance, [18][19][20][21][22] significantly augments PGRN expression in 3T3-L1 adipocytes.…”

Section: Introductionmentioning

confidence: 99%

Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

Zhou

Liu

et al. 2015

Cell Cycle

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Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the direct effects of PGRN in vivo and the underlying mechanisms between PGRN and impaired insulin sensitivity are not fully understood. In this study, mice treated with PGRN for 21 d exhibited the impaired glucose tolerance and insulin sensitivity, remarkable ER stress as well as attenuated insulin signaling in liver and adipose tissue but not in skeletal muscle. Furthermore, treatment of mice with phenyl butyric acid (PBA), a chemical chaperone alleviating ER stress, resulted in a significant restoration of systemic insulin sensitivity and recovery of insulin signaling induced by PGRN. Consistent with these findings in vivo, we also observed that PGRN treatment induced ER stress, impaired insulin signaling in cultured hepatocytes and adipocytes, with such effects being partially nullified by blockade of PERK. Whereas PGRN-deficient hepatocytes and adipocytes were more refractory to palmitate-induced insulin resistance, indicating the causative role of the PERK-eIF2a axis of the ER stress response in action of PGRN. Collectively, our findings supported the notion that PGRN is a key regulator of insulin resistance and that PGRN may mediate its effects, at least in part, by inducing ER stress via the PERK-eIF2a dependent pathway.

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Granulin epithelin precursor: a bone morphogenic protein 2‐inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis

Cited by 112 publications

References 70 publications

ATF6a, a Runx2-activable transcription factor, is a novel regulator of chondrocyte hypertrophy

ATF6a, a Runx2-activable transcription factor, is a novel regulator of chondrocyte hypertrophy

Adipose Tissue as an Endocrine Organ: An Update on Pro-inflammatory and Anti-inflammatory Microenvironment

Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

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