Histone Deacetylase 3 Suppression Increases PH Domain and Leucine-rich Repeat Phosphatase (Phlpp)1 Expression in Chondrocytes to Suppress Akt Signaling and Matrix Secretion

Bradley, Elizabeth W.; Carpio, Lomeli R.; Westendorf, Jennifer J.

doi:10.1074/jbc.m112.423723

Cited by 75 publications

(83 citation statements)

References 54 publications

(19 reference statements)

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“…This fact is particularly interesting taking into account the fact that mTOR signaling can be activated by IGF-1 signaling and is active during growth plate development also has been shown to regulate cell size. 35 IGF-2 is the other ligand that can bind to the IGF1R. This paternal imprinted gene has been shown to have a role in skeletal development.…”

Section: Igf-1 and Chondrocytesmentioning

confidence: 99%

IGF-1 regulation of key signaling pathways in bone

2013

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Insulin-like growth factor 1 (IGF-1) is an unique peptide that functions in an endocrine/paracrine and autocrine manner in most tissues. Although it was postulated initially that liver-derived IGF-1 was the major source of IGF-1 (that is, the somatomedin hypothesis), it is also produced in a wide variety of tissues and can function in numerous ways as both a proliferative and differentiative factor. One such tissue is bone and all cell lineages in the skeleton have been shown to not only require IGF-1 for normal development and function but also to respond to IGF-1 via the IGF-1 receptor. Ligandreceptor activation leads to several distinct downstream signaling cascades, which have significant implications for cell survival, protein synthesis and energy utilization. The novel role of IGF-1 in regulating metabolic demands of the bone remodeling unit is currently under investigation. More studies are likely to shed new light on various aspects of skeletal physiology and potentially may lead to new therapeutics.

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Section: Igf-1 and Chondrocytesmentioning

confidence: 99%

IGF-1 regulation of key signaling pathways in bone

2013

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“…We previously demonstrated that Hdac3 also suppresses chondrocyte hypertrophy (3). Deletion of Hdac3 in osteo/ chondroprogenitor cells and committed osteoblasts reduces bone mass (4,5).…”

Section: Discussionmentioning

confidence: 99%

“…The resulting cell suspension was placed into micromasses consisting of 2 ϫ 10 5 cells in a 10 l drop of DMEM. After 1 h, chondrogenic medium (DMEM, supplemented with 5% FBS, 1% antimycotic/antibiotic and 1ϫ mixture of insulin, transferrin, and selenium (ITS) (Invitrogen, Carlsbad, CA)) was added to the cultures for the indicated periods of time (3,25,26). Cells were infected with adenoviral (Ad)-GFP or Ad-Cre (MOI ϭ 10) on day 0 and harvested for analysis on day 3.…”

Section: Generation Of Hdac7mentioning

confidence: 99%

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Histone Deacetylase 7 (Hdac7) Suppresses Chondrocyte Proliferation and β-Catenin Activity during Endochondral Ossification

Bradley

Carpio

Olson

et al. 2015

Journal of Biological Chemistry

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Background: Hdac7 is a transcriptional co-repressor in skeletal tissues, but its role in chondrocytes is undefined. Results: Proteasomal degradation reduced Hdac7 levels during chondrogenic maturation and conditional deletion of Hdac7 in chondrocytes increased proliferation and ␤-catenin levels. Conclusion: Hdac7 degradation enhances ␤-catenin transcriptional activity in growth plate chondrocytes. Significance: Suppressing Hdac7 levels increases chondrocyte proliferation and promotes cartilage formation and regeneration.

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“…This possibility proclaims that PHLPP directly modifies histones on these specific promoters (Reyes et al 2014) Moreover, HDAC inhibitors regulate the expression of PHLPP1. A study demonstrated that HDAC3 upon association with PHLPP1 promoter region controls chondrocyte hypertrophy and matrix content by activating AKT through repressing PHLPP1 expression (Bradley et al 2013). During chondriogenesis, stimulation with TGFβ, a potent activator of chondrogenesis, causes HDAC3 association with the PHLPP1 promoter leading to decreased transcription of PHLPP1.…”

Section: Post-translational Modifications By Phlpp Regulate the Epigementioning

confidence: 99%

PHLPP: a putative cellular target during insulin resistance and type 2 diabetes

Mathur

Pandey

Kakkar

2017

Journal of Endocrinology

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Progressive research in the past decade converges to the impact of PHLPP in regulating the cellular metabolism through PI3K/AKT inhibition. Aberrations in PKB/AKT signaling coordinates with impaired insulin secretion and insulin resistance, identified during T2D, obesity and cardiovascular disorders which brings in the relevance of PHLPPs in the metabolic paradigm. In this review, we discuss the impact of PHLPP isoforms in insulin signaling and its associated cellular events including mitochondrial dysfunction, DNA damage, autophagy and cell death. The article highlights the plausible molecular targets that share the role during insulin-resistant states, whose understanding can be extended into treatment responses to facilitate targeted drug discovery for T2D and allied metabolic syndromes.

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Histone Deacetylase 3 Suppression Increases PH Domain and Leucine-rich Repeat Phosphatase (Phlpp)1 Expression in Chondrocytes to Suppress Akt Signaling and Matrix Secretion

Cited by 75 publications

References 54 publications

IGF-1 regulation of key signaling pathways in bone

IGF-1 regulation of key signaling pathways in bone

Histone Deacetylase 7 (Hdac7) Suppresses Chondrocyte Proliferation and β-Catenin Activity during Endochondral Ossification

PHLPP: a putative cellular target during insulin resistance and type 2 diabetes

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