The spatial and temporal regulation of the hormonal signal. Role of mitochondria in the formation of a protein complex required for the activation of cholesterol transport and steroids synthesis

AbstractCholesterol has long been suspected of influencing hair biology, with dysregulated homeostasis implicated in several disorders of hair growth and cycling. Cholesterol transport proteins play a vital role in the control of cellular cholesterol levels and compartmentalisation. This research aimed to determine the cellular localisation, transport capability and regulatory control of cholesterol transport proteins across the hair cycle. Immunofluorescence microscopy in human hair follicle sections revealed differential expression of ATP-binding cassette (ABC) transporters across the hair cycle. Cholesterol transporter expression (ABCA1, ABCG1, ABCA5 and SCARB1) reduced as hair follicles transitioned from growth to regression. Staining for free cholesterol (filipin) revealed prominent cholesterol striations within the basement membrane of the hair bulb. Liver X receptor agonism demonstrated active regulation of ABCA1 and ABCG1, but not ABCA5 or SCARB1 in human hair follicles and primary keratinocytes. These results demonstrate the capacity of human hair follicles for cholesterol transport and trafficking. Future studies examining the role of cholesterol transport across the hair cycle may shed light on the role of lipid homeostasis in human hair disorders.

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A Pivotal Role of the Basic Leucine Zipper Transcription Factor bZIP53 in the Regulation of Arabidopsis Seed Maturation Gene Expression Based on Heterodimerization and Protein Complex Formation

The Plant Cell ◽

10.1105/tpc.108.062968 ◽

2009 ◽

Vol 21 (6) ◽

pp. 1747-1761 ◽

Cited By ~ 109

Author(s):

Rosario Alonso ◽

Luis Oñate-Sánchez ◽

Fridtjof Weltmeier ◽

Andrea Ehlert ◽

Isabel Diaz ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Complex Formation ◽

Protein Complex ◽

Leucine Zipper ◽

Pivotal Role ◽

Basic Leucine Zipper ◽

Arabidopsis Seed ◽

Protein Complex Formation

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The Role of Maternal-Fetal Cholesterol Transport in Early Fetal Life: Current Insights1

Biology of Reproduction ◽

10.1095/biolreprod.112.102442 ◽

2013 ◽

Vol 88 (1) ◽

Cited By ~ 69

Author(s):

Maria E. Baardman ◽

Wilhelmina S. Kerstjens-Frederikse ◽

Rolf M.F. Berger ◽

Marian K. Bakker ◽

Robert M.W. Hofstra ◽

...

Keyword(s):

Cholesterol Transport ◽

Fetal Life

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BRN2 is a non-canonical melanoma tumor-suppressor

Nature Communications ◽

10.1038/s41467-021-23973-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Michael Hamm ◽

Pierre Sohier ◽

Valérie Petit ◽

Jérémy H. Raymond ◽

Véronique Delmas ◽

...

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Tumor Suppressor ◽

The Other ◽

Pi3k Signaling ◽

Melanoma Tumor ◽

Temporal Regulation ◽

Metastatic Colonization ◽

Pou Domain

AbstractWhile the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600EPtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.

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Gasdermin D mediates inflammation-induced defects in reverse cholesterol transport and promotes atherosclerosis.

10.1101/2021.04.16.440183 ◽

2021 ◽

Author(s):

Emmanuel Opoku ◽

Cynthia Alicia Traughber ◽

David Zhang ◽

Amanda J Iacano ◽

Mariam Khan ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Reverse Cholesterol Transport ◽

Foam Cell ◽

Atherosclerotic Lesion ◽

Foam Cell Formation ◽

Cholesterol Transport ◽

Inflammasome Activation ◽

Lesion Area ◽

Direct Role

Nlrp3 inflammasome is activated in advanced human atherosclerotic plaques. Gasdermin D (GsdmD) serves as a final executor of Nlrp3 inflammasome activity, by generating membrane pores for the release of mature Interleukin-1beta (IL-b). Inflammation dampens reverse cholesterol transport (RCT) and promotes atherogenesis, while anti-IL-1b; antibodies were shown to reduce cardiovascular disease in humans. Though Nlrp3/IL-1b; nexus is an emerging atherogenic pathway, the direct role of GsdmD in atherosclerosis is not yet clear. Here, we used in-vivo Nlrp3 inflammasome activation to show that the GsdmD-/- mice release ~80% less IL-1b; vs WT mice. The GsdmD-/- macrophages were more resistant to Nlrp3 inflammasome mediated reduction in cholesterol efflux, showing ~26% decrease vs. ~60% reduction in WT macrophages. GsdmD expression in macrophages exacerbated foam cell formation in an IL-1b; dependent fashion. The GsdmD-/- mice were resistance to Nlrp3 inflammasome mediated defect in RCT, with ~32% reduction in plasma RCT vs. ~ 57% reduction in WT mice, ~ 17% reduction in RCT to liver vs. 42% in WT mice, and ~ 37% decrease in RCT to feces vs. ~ 61% in WT mice. The LDLr anti-sense oligonucleotides (ASO) induced hyperlipidemic mouse model showed role of GsdmD in promoting atherosclerosis. The GsdmD-/- mice exhibit ~42% decreased atherosclerotic lesion area in females and ~33% decreased lesion area in males vs. WT mice. The atherosclerotic plaque-bearing WT mice showed the presence of cleaved N-terminal fragment of GsdmD, indicating cleavage of GsdmD during atherosclerosis. Our data show that GsdmD mediates inflammation-induced defect in RCT and promotes atherosclerosis.

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Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain

eLife ◽

10.7554/elife.51977 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 4

Author(s):

Hui Ye ◽

Shamsideen A Ojelade ◽

David Li-Kroeger ◽

Zhongyuan Zuo ◽

Liping Wang ◽

...

Keyword(s):

Synaptic Transmission ◽

Protein Complex ◽

Adult Brain ◽

Aging Brain ◽

Gtpase Activating Protein ◽

Ultrastructural Evidence ◽

Aging Adults ◽

And Function ◽

Brain Homeostasis

Retromer, including Vps35, Vps26, and Vps29, is a protein complex responsible for recycling proteins within the endolysosomal pathway. Although implicated in both Parkinson’s and Alzheimer’s disease, our understanding of retromer function in the adult brain remains limited, in part because Vps35 and Vps26 are essential for development. In Drosophila, we find that Vps29 is dispensable for embryogenesis but required for retromer function in aging adults, including for synaptic transmission, survival, and locomotion. Unexpectedly, in Vps29 mutants, Vps35 and Vps26 proteins are normally expressed and associated, but retromer is mislocalized from neuropil to soma with the Rab7 GTPase. Further, Vps29 phenotypes are suppressed by reducing Rab7 or overexpressing the GTPase activating protein, TBC1D5. With aging, retromer insufficiency triggers progressive endolysosomal dysfunction, with ultrastructural evidence of impaired substrate clearance and lysosomal stress. Our results reveal the role of Vps29 in retromer localization and function, highlighting requirements for brain homeostasis in aging.

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