Biomedical subjects

Chunjiang Yu

Publications and source records attributed to Chunjiang Yu.

7 recordsLinked to original sources

PubMed2005

The small heat shock protein alpha B-crystallin is a novel inhibitor of TRAIL-induced apoptosis that suppresses the activation of caspase-3.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor alpha family of cytokines that preferentially induces apoptosis in transformed cells, making it a promising cancer therapy. However, many neoplasms are resistant to TRAIL-induced apoptosis by mechanisms that are poorly understood. We demonstrate that the expression of the small heat shock protein alpha B-crystallin (but not other heat shock proteins or apoptosis-regulating proteins) correlates with TRAIL resistance in a panel of human cancer cell lines. Stable expression of wild-type alpha B-crystallin, but not a pseudophosphorylation mutant impaired in its assembly and chaperone function, protects cancer cells from TRAIL-induced caspase-3 activation and apoptosis in vitro. Furthermore, selective inhibition of alpha B-crystallin expression by RNA interference sensitizes cancer cells to TRAIL. In addition, wild-type alpha B-crystallin promotes xenograft tumor growth and inhibits TRAIL-induced apoptosis in vivo in nude mice, whereas a pseudophosphorylation alpha B-crystallin mutant impaired in its anti-apoptotic function inhibits xenograft tumor growth. Collectively, these findings indicate that alpha B-crystallin is a novel regulator of TRAIL-induced apoptosis and tumor growth. Moreover, these results demonstrate that targeted inhibition of alpha B-crystallin promotes TRAIL-induced apoptosis, thereby suggesting a novel strategy to overcome TRAIL resistance in cancer.

Apoptosis↗

PubMed2004

Peroxisome proliferator-activated receptor gamma agonists promote TRAIL-induced apoptosis by reducing survivin levels via cyclin D3 repression and cell cycle arrest.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapy that preferentially induces apoptosis in cancer cells. However, many neoplasms are resistant to TRAIL by mechanisms that are poorly understood. Here we demonstrate that human breast cancer cells, but not normal mammary epithelial cells, are dramatically sensitized to TRAIL-induced apoptosis and caspase activation by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists of the thiazolidinedione (TZD) class. Although TZDs do not significantly alter the expression of components of the TRAIL signaling pathway, they profoundly reduce protein levels of cyclin D3, but not other D-type cyclins, by decreasing cyclin D3 mRNA levels and by inducing its proteasomal degradation. Importantly, both TRAIL sensitization and reduction in cyclin D3 protein levels induced by TZDs are likely PPARgamma-independent because a dominant negative mutant of PPARgamma did not antagonize these effects of TZDs, nor were they affected by the expression levels of PPARgamma. TZDs also inhibit G(1) to S cell cycle progression. Furthermore, silencing cyclin D3 by RNA interference inhibits S phase entry and sensitizes breast cancer cells to TRAIL, indicating a key role for cyclin D3 repression in these events. G(1) cell cycle arrest sensitizes breast cancer cells to TRAIL at least in part by reducing levels of the anti-apoptotic protein survivin: ectopic expression of survivin partially suppresses apoptosis induced by TRAIL and TZDs. We also demonstrate for the first time that TZDs promote TRAIL-induced apoptosis of breast cancer in vivo, suggesting that this combination may be an effective therapy for cancer.

Apoptosis↗

PubMed2003

Regulated hyperaccumulation of presenilin-1 and the "gamma-secretase" complex. Evidence for differential intramembranous processing of transmembrane subatrates.

Intramembranous "gamma-secretase" processing of beta-amyloid precursor protein (APP) and other transmembrane proteins, including Notch, is mediated by a macromolecular complex consisting of presenilins (PSs), nicastrin (NCT), APH-1, and PEN-2. We now demonstrate that in cells coexpressing PS1, APH-1, and NCT, full-length PS1 accumulates to high levels and is fairly stable. Upon expression of PEN-2, the levels of PS1 holoprotein are significantly reduced, commensurate with an elevation in levels of PS1 fragments. These findings suggest that APH-1 and NCT are necessary for stabilization of full-length PS1 and that PEN-2 is critical for the proteolysis of stabilized PS1. In N2a and 293 cell lines that stably overexpress PS1, APH-1, NCT, and PEN-2, PS1 fragment levels are elevated by up to 10-fold over endogenous levels. In these cells, we find a marked accumulation of the APP-CTF gamma (AICD) fragment and a concomitant reduction in levels of both APP-CTF beta and CTF alpha. Moreover, the production of the gamma-secretase-generated Notch S3/NICD derivative is modestly elevated. However, we failed to observe a corresponding increase in levels of secreted A beta peptides in the medium of these cells. These results lead us to conclude that, although the PS1, APH-1, NCT, and PEN-2 are essential for gamma-secretase activity, the proteolysis of APP-CTF and Notch S2/NEXT are differentially regulated and require the activity of additional cofactors that promote production of AICD, NICD, and A beta.

Amyloid Precursor Protein Secretases↗

PubMed2003

Cholesterol is superior to 7-ketocholesterol or 7 alpha-hydroxycholesterol as an allosteric activator for acyl-coenzyme A:cholesterol acyltransferase 1.

We compared the abilities of cholesterol versus various oxysterols as substrate and/or as activator for the enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT), by monitoring the activity of purified human ACAT1 in response to sterols solubilized in mixed micelles or in reconstituted vesicles. The results showed that 5 alpha,6 alpha-epoxycholesterol and 7 alpha-hydroxycholesterol are comparable with cholesterol as the favored substrates, whereas 7-ketocholesterol, 7 beta-hydroxycholesterol, 5 beta,6 beta-epoxycholesterol, and 24(S),25-epoxycholesterol are very poor substrates for the enzyme. We then tested the ability of 7-ketocholesterol as an activator when cholesterol was measured as the substrate, and vice versa. When cholesterol was measured as the substrate, the addition of 7-ketocholesterol could not activate the enzyme. In contrast, when 7-ketocholesterol was measured as the substrate, the addition of cholesterol significantly activated the enzyme and changed the shape of the substrate saturation curve from sigmoidal to essentially hyperbolic. Additional results show that, as an activator, cholesterol is much better than all the oxysterols tested. These results suggest that ACAT1 contains two types of sterol binding sites; the structural requirement for the ACAT activator site is more stringent than it is for the ACAT substrate site. Upon activation by cholesterol, ACAT1 becomes promiscuous toward various sterols as its substrate.

Allosteric Regulation↗

PubMed2002

Role of the N-terminal hydrophilic domain of acyl-coenzyme A:cholesterol acyltransferase 1 on the enzyme's quaternary structure and catalytic efficiency.

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) is an enzyme involved in cellular cholesterol homeostasis and atherosclerosis. ACAT1 is an allosteric enzyme responding to its substrate cholesterol in a sigmoidal manner. It is a homotetrameric protein that spans the membrane multiple times, with its N-terminal 131 hydrophilic amino acids residing at the cytoplasmic side of the endoplasmic reticulum. This region contains two closely linked putative alpha-helices. Our current studies show that this region contains a dimer-forming motif. Adding this motif to the bacterial glutathione S-transferase (GST) converted the homodimeric GST to a tetrameric fusion protein. Conversely, deleting this motif from the full-length ACAT1 converted the enzyme from a homotetramer to a homodimer. The dimeric ACAT1 remains enzymatically active. Its biochemical characteristics, including the sigmoidal response to cholesterol, the IC(50) value toward a specific ACAT inhibitor, and sensitivity toward heat inactivation, are essentially unaltered. On the other hand, the dimeric ACAT1 exhibits a 5-10-fold increase in the V(max) of the overall reaction and a 2.2-fold increase in the K(m) for oleoyl-coenzyme. Thus, deleting the dimer-forming motif near the N-terminus changes ACAT1 from its tetrameric form to a dimeric form and increases its catalytic efficiency.

Allosteric Regulation↗

PubMed2002

[Microanatomy study on sinus triangle region].

OBJECTIVES: To explore shape and position relationship of the structures with in sinus triangle region, and provide the anatomic foundation for extended presigmoid operative approach. METHODS: Ten cadaveric heads and 15 skull-base specimens fixed with 10% formalin, with aid of operative microscope, the shape and relations of structures with in the sinus triangle region were observed and microphotographed. Four cadaveric heads were sectioned in different plane using collodion embedding process. RESULTS: Jugular blub (JB) had high -placed jugular blub (HJB), normal jugular blub (NJB) and low-placed jugular blub (LJB). The incidence of HJB was 8% and 18% for the left and right sides (P < 0.01). The JB dome can extend upward the hypotympanic cavity and the posterior wall of the internal acoustic meatus. The incidence of NJB and LJB was 36% and 30%, and 6% and 2% respectively. The level distance between the posterior semicircular canal and petrosal posterior surface was (4.1 +/- 1.1) mm. The distance between the JB and vertical part of the facial nerve was (3.2 +/- 0.5) mm and (2.0 +/- 0.4) mm. The distance between the JB and posterior margin of the internal acoustic port was (7.5 +/- 1.7) mm and (4.0 +/- 1.0) mm. CONCLUSIONS: Knowing the shape and position relationship of structures in the sinus triangle region is favorable for preserving the important structures in extended presigmoid operative approach.

Autopsy↗

PubMed2002

[Microsurgical anatomy of craniocervical junction region].

OBJECTIVES: To study the shape and the structures in the craniocervical junction region (CCJR) and the safety of far lateral approach. METHODS: Ten cadaveric heads and 20 skull-base specimens were fixed with 10% formalin, and 4 of the 10 cadaveric heads were sectioned in different plane with the aid of operative microscope. The shape and relation of structures in the CCJR were observed. RESULTS: The third segment of the vertebral artery(VA) was 21.6(15.3 31.9) mm. An incomplete bony canal was found to be 15% and complete bony canal surrounding the VA to be 5% on the VA groove. The distance of the left and right VA was 14.3a(c)(9.8 15.2) mm on the entry into the dura. The length of the occipital condyle was 26.8(25.1 28.2) mm, with the thickness of its anterior, middle and posterior one-third part was 9.9(9.6 10.6) mm, 11.2(9.2 13.1) mm and 8.6 (8.3 9.0) mm respectively. The distance between the posterior pole of the occipital condyle and the intracranial orifice of the hypoglossal canal was 9.9(8.6 11.4) mm, and between the posterior pole and the extracranial orifice was 16.1(13.5 17.1) mm. The transverse process of the atlas was the most important bony landmark for the approach. CONCLUSIONS: Knowing the shape and relationship of the VA and occipital condyle in the CCJR is helpful in preserving the important structures in far lateral approach to target region.

Humans↗