Biomedical subjects

X J Yang

Publications and source records attributed to X J Yang.

At least 19 recordsLinked to original sources

PubMed2001

Regulation of global acetylation in mitosis through loss of histone acetyltransferases and deacetylases from chromatin.

Histone acetylation, a reversible modification of the core histones, is widely accepted to be involved in remodeling chromatin organization for genetic reprogramming. Histone acetylation is a dynamic process that is regulated by two classes of enzymes, the histone acetyltransferases (HATs) and histone deacetylases (HDACs). Although promoter-specific acetylation and deacetylation has received most of the recent attention, it is superimposed upon a broader acting and dynamic acetylation that profoundly affects many nuclear processes. In this study, we monitored this broader histone acetylation as cells enter and exit mitosis. In contrast to the hypothesis that HATs and HDACs remain bound to mitotic chromosomes to provide an epigenetic imprint for postmitotic reactivation of the genome, we observed that HATs and HDACs are spatially reorganized and displaced from condensing chromosomes as cells progress through mitosis. During mitosis, HATs and HDACs are unable to acetylate or deacetylate chromatin in situ despite remaining fully catalytically active when isolated from mitotic cells and assayed in vitro. Our results demonstrate that HATs and HDACs do not stably bind to the genome to function as an epigenetic mechanism of selective postmitotic gene activation. Our results, however, do support a role for spatial organization of these enzymes within the cell nucleus and their relationship to euchromatin and heterochromatin postmitotically in the reactivation of the genome.

Acetylation↗

PubMed2001

Temporal and spatial effects of Sonic hedgehog signaling in chick eye morphogenesis.

Proper dorsal--ventral pattern formation of the optic cup is essential for vertebrate eye morphogenesis and retinotectal topographic mapping. Previous studies have suggested that midline tissue-derived Sonic hedgehog (Shh) molecules play critical roles in establishing the bilateral eye fields and in determining the proximal--distal axis of the eye primordium. Here, we have examined the temporal requirements for Shh during the optic vesicle to optic cup transition and after early optic cup formation in chick embryos. Both misexpressing Shh by virus and blocking Shh activity by antibodies resulted in disruption of ventral ocular tissues. Decreasing endogenous Shh signals unexpectedly revealed a sharp morphological boundary subdividing dorsal and ventral portions of the optic cup. In addition, Shh signals differentially influenced expression patterns of genes involved in ocular tissue specification (Pax6, Pax2, and Otx2) and dorsal--ventral patterning (cVax) within the ventral but not dorsal optic cup. Ectopic Shh suppressed expression of Bone Morphogenetic Protein 4 (BMP4) in the dorsal retina, whereas reducing endogenous Sonic hedgehog activity resulted in a ventral expansion of BMP4 territory. These results demonstrate that temporal requirements for Shh signals persist after the formation of the optic cup and suggest that the early vertebrate optic primordium may be subdivided into dorsal and ventral compartments. We propose a model in which ventrally derived Shh signals and dorsally restricted BMP4 signals act antagonistically to regulate the growth and specification of the optic primordium.

Animals↗

PubMed2001

The monocytic leukemia zinc finger protein MOZ is a histone acetyltransferase.

The monocytic leukemia zinc finger protein (MOZ) gene is rearranged in t(8;16)(p11;p13), t(8;22)(p11;q13) and inv(8)(p11q13) associated with acute myeloid leukemia. The other fusion partners involved are CBP, p300 and TIF2, transcriptional coactivators with known or potential histone acetyltransferase (HAT) activity. MOZ itself is a 2004-residue protein containing a putative acetyl CoA-binding motif, so it was hypothesized that MOZ is a HAT. Here we present direct evidence that MOZ has intrinsic HAT activity. Moreover, MOZ possesses a transcriptional repression domain at its N-terminal part and an activation domain at its C-terminal part. The activation domain does not show sequence similarity to any yeast proteins, but when tethered, it is able to activate transcription in yeast. Therefore, MOZ is a HAT with characteristics of a transcriptional coregulator, supporting the hypothesis that aberrant acetylation by abnormal MOZ proteins leads to leukemogenesis.

Acetyltransferases↗

PubMed2001

Full term development of rabbit oocytes fertilized by intracytoplasmic sperm injection.

Intracytoplasmic sperm injection (ICSI) has been applied successfully in the treatment of male infertility in humans and in fertilization research in mice. However, the technique has had limited success in producing offspring in other species including the rabbit. The aim of this research was to test the in vitro and in vivo developmental of rabbit oocytes after ICSI. Sperm used for ICSI were collected from mature Dutch Belted buck and washed 2-3 times with PBS +0.1% polyvinyl alcohol (PVA) and then mixed with 10% polyvinyl pyrrolidone (PVP) prior to microinjection. Oocytes were collected from superovulated does 14-15 hr after hCG injection and were fertilized by microinjection of a single sperm into the ooplasm of each oocyte without additional activation treatment. After ICSI, the presumed zygotes were either cultured in KSOM +0.3% BSA for 4 days or transferred into oviducts of recipient does at the pronuclear or 2-cell stage. A high percentage of fertilization (78%, n = 114) and blastocyst development (39%) was obtained after ICSI. Control oocytes, receiving a sham injection, exhibited a lower activation rate (31%, n = 51) and were unable to develop to the blastocyst stage, suggesting that the blastocysts developed following ICSI were derived from successful fertilization rather than parthenogenetic development. A total of 113 embryos were transferred to six recipient does. Two recipients became pregnant and delivered seven live young. Our results demonstrated that rabbit oocytes can be successfully fertilized and activated by ICSI and can result in the birth of live offspring.

Animals↗

PubMed2001

High-grade prostatic intraepithelial neoplasia with adjacent atypia is associated with a higher incidence of cancer on subsequent needle biopsy than high-grade prostatic intraepithelial neoplasia alone.

OBJECTIVES: High-grade prostatic intraepithelial neoplasia (HGPIN) is often considered a premalignant lesion of the prostate. Its incidence ranges from 0.7% to 20% in all prostate biopsies, and patients with HGPIN on initial biopsy are reportedly found to have a higher risk of cancer on subsequent biopsy. The purpose of our study was to determine the incidence of HGPIN in our patients who underwent prostate biopsy and to determine whether a further pathologic subclassification of HGPIN between HGPIN alone and HGPIN with adjacent atypical glands has any prognostic value in predicting the rate of prostate cancer on subsequent prostate biopsy. METHODS: A total of 485 patients who underwent prostate biopsy between January 1998 and October 1999 were included in the study. Each set of slides was reviewed by a single urologic pathologist to determine the presence of HGPIN alone or HGPIN with adjacent atypical glands. If any HGPIN was identified, a repeat biopsy was performed, and the presence of cancer was recorded. RESULTS: The overall incidence of HGPIN alone and HGPIN with adjacent atypical glands on initial biopsy was 33 (6.8%) of 485. Of these 33 patients, 21 (64%) had HGPIN alone and 12 (36%) had HGPIN with adjacent atypical glands. Three (14%) of 21 patients with HGPIN alone were found to have cancer on subsequent biopsy compared to 9 (75%) of 12 patients with HGPIN with adjacent atypia on initial biopsy. This difference is statistically significant (P <0.005). CONCLUSIONS: The incidence of HGPIN alone in our experience is 4.3% (21 of 485). Patients with HGPIN with adjacent atypical glands suspicious for cancer have a significantly higher incidence of cancer on subsequent biopsy than patients with HGPIN alone.

Aged↗

PubMed2001

Correlation between biopsy and radical cystectomy in assessing grade and depth of invasion in bladder urothelial carcinoma.

OBJECTIVES: To assess the degree of correlation between the pathologic characteristics of the specimens obtained from biopsy and radical cystoprostatectomy. The stage and grade of bladder urothelial (transitional cell) carcinoma are important predictors of prognosis. METHODS: We retrospectively identified 169 cases of urothelial carcinoma from 222 radical cystectomies performed at University of Chicago Hospitals from 1992 to 1999. RESULTS: For all the cases in this study, the histologic grade, using the 1998 World Health Organization and International Society of Urological Pathologists (WHO/ISUP) classification, was identical when the biopsy specimen and radical cystectomy specimen were compared. However, when the same cases were assessed using the traditional three-grade system, the histologic grade increased or decreased by one grade in 19 (11%) and 8 (5%) of 169 cases, respectively. Patients with invasion of the lamina propria on biopsy had tumor extending outside the bladder in 15 (27%) of 55 cases. Patients with invasion of the muscularis propria on biopsy had tumor extending outside the bladder in 47 (49%) of 96 cases, including nodal metastasis in 22 (23%) of 96 cases. Overall, bladder biopsy underestimated the true extent of the disease in 78 (46%) of 169 cases. CONCLUSIONS: Using either the WHO/ISUP (1998) classification or the traditional three-grade system, the histologic grade of the biopsy specimen is a fairly good predictor of the final histologic grade. The preoperative biopsy tends to understage bladder cancer. Patients with muscularis propria invasion demonstrated by biopsy have a significantly higher risk of non-organ-confined disease than those with lamina propria invasion.

Aged↗

PubMed2001

The Bacillus subtilis RNase P holoenzyme contains two RNase P RNA and two RNase P protein subunits.

Ribonuclease P (RNase P) catalyzes the 5' maturation of precursor tRNA transcripts and, in bacteria, is composed of a catalytic RNA and a protein. We investigated the oligomerization state and the shape of the RNA alone and the holoenzyme of Bacillus subtilis RNase P in the absence of substrate by synchrotron small-angle X-ray scattering and affinity retention. The B. subtilis RNase P RNA alone is a monomer; however, the scattering profile changes upon the addition of monovalent ions, possibly suggesting different interdomain angles. To our surprise, the X-ray scattering data combined with the affinity retention results indicate that the holoenzyme contains two RNase P RNA and two RNase P protein molecules. We propose a structural model of the holoenzyme with a symmetrical arrangement of the two RNA subunits, consistent with the X-ray scattering results. This (P RNA)2(P protein)2 complex likely binds substrate differently than the conventional (P RNA)1(P protein)1 complex; therefore, the function of the B. subtilis RNase P holoenzyme may be more diverse than previously thought. These revisions to our knowledge of the RNase P holoenzyme suggest a more versatile role for proteins in ribonucleoprotein complexes.

Avidin↗

PubMed2001

Prostatic foamy gland carcinoma with aggressive behavior: clinicopathologic, immunohistochemical, and ultrastructural analysis.

Foamy gland carcinoma is a recently described histologic variant of prostatic adenocarcinoma characterized by abundant foamy cytoplasm and minimal cytologic atypia. The biologic behavior and biochemical nature of the foamy adenocarcinoma cells are unknown. Six cases of prostatic adenocarcinoma with marked foamy appearance were identified from radical prostatectomies. Clinicopathologic, histochemical, immunohistochemical, and ultrastructural analyses were conducted. The patients ranged in age from 50 to 73 years (mean age, 65 years) with preoperative serum prostate-specific antigen levels ranging from 2.7 to 37.5 ng/mL (mean, 15.2 ng/mL). All six cases were bilateral high-volume tumors. Five of six patients had high-grade tumors with extraprostatic extension. The foamy tumor cells were negative for mucin and lipid stains, but were positive for colloidal iron and Alcian blue stain. Ultrastructurally, the foamy cells displayed numerous intracytoplasmic vesicles and numerous polyribosomes. The authors conclude that the foamy appearance of these tumor cells is the result of the presence of numerous intracytoplasmic vesicles, and not the result of the presence of lipid or neutral mucin. This study illustrates that foamy gland carcinoma is a distinctive histologic variant of prostatic adenocarcinoma and is often associated with an aggressive behavior despite its deceivingly benign histologic appearance.

Adenocarcinoma↗

PubMed2001

Immunohistochemical distinction between primary adenocarcinoma of the bladder and secondary colorectal adenocarcinoma.

Primary adenocarcinoma of the urinary bladder sometimes causes a diagnostic dilemma because it can be indistinguishable morphologically from adenocarcinoma of colorectal origin secondarily involving the bladder by metastasis or direct extension. It is much less well studied than conventional urothelial carcinoma and colorectal adenocarcinoma because of its rarity. The current study was specifically designed to investigate whether an important mechanism involved in the pathogenesis of colorectal adenocarcinoma, beta-catenin dysregulation, was also important for the development of primary bladder adenocarcinoma and whether these two morphologically similar tumors could be distinguished immunohistochemically. Formalin-fixed, paraffin-embedded tissues from 17 primary adenocarcinomas of the urinary bladder, 16 colorectal adenocarcinomas involving the bladder, and 10 conventional urothelial (transitional) carcinomas were included in this study. Thirteen of the primary bladder adenocarcinomas were moderately to well differentiated (enteric type) and morphologically indistinguishable from colorectal cancers. The remaining four primary tumors were poorly differentiated (two cases) or of clear cell type (two cases). Immunohistochemical studies using a panel of monoclonal antibodies demonstrated positive nuclear staining for beta-catenin expression in 13 of the 16 (81%) colorectal adenocarcinomas secondarily involving the bladder but in none of the primary adenocarcinomas or the urothelial carcinomas. Instead, positive membranous (and some cytoplasmic) staining was present in all primary bladder tumors with the exception of two poorly differentiated adenocarcinomas where no beta-catenin staining was detected. All secondary colorectal adenocarcinomas stained negatively for CK7 and thrombomodulin (TM), whereas positivity for CK20 was observed in 15 (94%) cases. All urothelial carcinomas stained positively for CK7 and TM, and four of them also for CK20. Primary adenocarcinomas of the bladder showed mixed staining patterns for CK7, CK20, and TM with a positive rate of 65%, 53%, and 59%, respectively. These data indicate that dysregulation of beta-catenin, an important aberration seen in colorectal carcinogenesis, does not appear to play a role in the pathogenesis of the bladder adenocarcinoma. In addition, our data demonstrate that a panel of immunostains, including CK7, CK20, TM, and beta-catenin, is of diagnostic value in differentiating primary bladder adenocarcinoma from secondary adenocarcinoma of colorectal origin.

Adenocarcinoma↗

PubMed2001

Histone deacetylase 4 possesses intrinsic nuclear import and export signals.

Nucleocytoplasmic trafficking of histone deacetylase 4 (HDAC4) plays an important role in regulating its function, and binding of 14-3-3 proteins is necessary for its cytoplasmic retention. Here, we report the identification of nuclear import and export sequences of HDAC4. While its N-terminal 118 residues modulate the nuclear localization, residues 244 to 279 constitute an authentic, strong nuclear localization signal. Mutational analysis of this signal revealed that three arginine-lysine clusters are necessary for its nuclear import activity. As for nuclear export, leucine-rich sequences located in the middle part of HDAC4 do not function as nuclear export signals. By contrast, a hydrophobic motif (MXXLXVXV) located at the C-terminal end serves as a nuclear export signal that is necessary for cytoplasmic retention of HDAC4. This motif is required for CRM1-mediated nuclear export of HDAC4. Furthermore, binding of 14-3-3 proteins promotes cytoplasmic localization of HDAC4 by both inhibiting its nuclear import and stimulating its nuclear export. Unlike wild-type HDAC4, a point mutant with abrogated MEF2-binding ability remains cytoplasmic upon exogenous expression of MEF2C, supporting the notion that direct MEF2 binding targets HDAC4 to the nucleus. Therefore, HDAC4 possesses intrinsic nuclear import and export signals for its dynamic nucleocytoplasmic shuttling, and association with 14-3-3 and MEF2 proteins affects such shuttling and thus directs HDAC4 to the cytoplasm and the nucleus, respectively.

3T3 Cells↗

PubMed2001

RBP1 recruits the mSIN3-histone deacetylase complex to the pocket of retinoblastoma tumor suppressor family proteins found in limited discrete regions of the nucleus at growth arrest.

Retinoblastoma (RB) tumor suppressor family pocket proteins induce cell cycle arrest by repressing transcription of E2F-regulated genes through both histone deacetylase (HDAC)-dependent and -independent mechanisms. In this study we have identified a stable complex that accounts for the recruitment of both repression activities to the pocket. One component of this complex is RBP1, a known pocket-binding protein that exhibits both HDAC-dependent and -independent repression functions. RB family proteins were shown to associate via the pocket with previously identified mSIN3-SAP30-HDAC complexes containing exclusively class I HDACs. Such enzymes do not interact directly with RB family proteins but rather utilize RBP1 to target the pocket. This mechanism was shown to account for the majority of RB-associated HDAC activity. We also show that in quiescent normal human cells this entire RBP1-mSIN3-SAP30-HDAC complex colocalizes with both RB family members and E2F4 in a limited number of discrete regions of the nucleus that in other studies have been shown to represent the initial origins of DNA replication following growth stimulation. These results suggest that RB family members, at least in part, drive exit from the cell cycle by recruitment of this HDAC complex via RBP1 to repress transcription from E2F-dependent promoters and possibly to alter chromatin structure at DNA origins.

Binding Sites↗

PubMed2001

Brain glucose-sensing mechanisms: ubiquitous silencing by aglycemia vs. hypothalamic neuroendocrine responses.

Interest in brain glucose-sensing mechanisms is motivated by two distinct neuronal responses to changes in glucose concentrations. One mechanism is global and ubiquitous in response to profound hypoglycemia, whereas the other mechanism is largely confined to specific hypothalamic neurons that respond to changes in glucose concentrations in the physiological range. Although both mechanisms use intracellular metabolism as an indicator of extracellular glucose concentration, the two mechanisms differ in key respects. Global hyperpolarization (inhibition) in response to 0 mM glucose can be reversed by pyruvate, implying that the reduction in ATP levels acting through ATP-dependent potassium (K-ATP) channels is the key metabolic signal for the global silencing in response to 0 mM glucose. In contrast, neuroendocrine hypothalamic responses in glucoresponsive and glucose-sensitive neurons (either excitation or inhibition, respectively) to physiological changes in glucose concentration appear to depend on glucokinase; neuroendocrine responses also depend on K-ATP channels, although the role of ATP itself is less clear. Lactate can substitute for glucose to produce these neuroendocrine effects, but pyruvate cannot, implying that NADH (possibly leading to anaplerotic production of malonyl-CoA) is a key metabolic signal for effects of glucose on glucoresponsive and glucose-sensitive hypothalamic neurons.

Adenosine Triphosphate↗

PubMed2001

Regulation of retinal ganglion cell production by Sonic hedgehog.

Previous work has shown that production of retinal ganglion cells is in part regulated by inhibitory factors secreted by ganglion cell themselves; however, the identities of these molecules are not known. Recent studies have demonstrated that the signaling molecule Sonic hedgehog (Shh) secreted by differentiated retinal ganglion cells is required to promote the progression of ganglion cell differentiation wave front and to induce its own expression. We present evidence that Shh signals play a role to negatively regulate ganglion cell genesis behind the differentiation wave front. Higher levels of Shh expression are detected behind the wave front as ganglion cells accumulate, while the Patched 1 receptor of Shh is expressed in adjacent retinal progenitor cells. Retroviral-mediated overexpression of Shh results in reduced ganglion cell proportions in vivo and in vitro. Conversely, inhibiting endogenous Shh activity by anti-Shh antibodies leads to an increased production of ganglion cells. Shh signals modulate ganglion cell production within the normal period of ganglion cell genesis in vitro without significantly affecting cell proliferation or cell death. Moreover, Shh signaling affects progenitor cell specification towards the ganglion cell fate during or soon after their last mitotic cycle. Thus, Shh derived from differentiated ganglion cells serves as a negative regulator behind the differentiation wave front to control ganglion cell genesis from the competent progenitor pool. Based on these results and other recent findings, we propose that Shh signals secreted by early-differentiated retinal neurons play dual roles at distinct concentration thresholds to orchestrate the progression of retinal neurogenic wave and the emergence of new neurons.

Animals↗

PubMed2001

Cerulenin mimics effects of leptin on metabolic rate, food intake, and body weight independent of the melanocortin system, but unlike leptin, cerulenin fails to block neuroendocrine effects of fasting.

Cerulenin and a related compound, C75, have recently been reported to reduce food intake and body weight independent of leptin through a mechanism hypothesized, like leptin, to involve hypothalamic nutrition-sensitive neurons. To assess whether these inhibitors act through mechanisms similar to mechanisms engaged by leptin, ob/ob and Ay (agouti) mice, as well as fed and fasted wild-type mice, were treated with cerulenin. Like leptin, cerulenin reduced body weight and food intake and increased metabolic rate in ob/ob mice, and cerulenin produced the same effects in wild-type mice, whereas lithium chloride, at doses that produce conditioned taste aversion, reduced metabolic rate. However, in contrast to leptin, cerulenin did not prevent effects of fasting on plasma corticosterone or hypothalamic levels of neuropeptide Y, agouti-related peptide, pro-opiomelanocortin, or cocaine- and amphetamine-related peptide mRNA. Also, in contrast to leptin, cerulenin was highly effective to reduce body weight in Ay mice, in which obesity is caused by blockade of the melanocortin receptor. These data demonstrate that cerulenin produces metabolic effects similar to effects of leptin, but through mechanisms that are independent of, or down-stream from, both leptin and melanocortin receptors.

Animals↗

PubMed2001

Removal and recovery of heavy metals from wastewaters by supported liquid membranes.

The removal and recovery of Cu, Cr and Zn from plating rinse wastewater using supported liquid membranes (SLM) are investigated. SLMs with specific organic extractants as the liquid membrane carriers in series are able to remove and concentrate heavy metals with very high purity, which is very promising for recycling of heavy metals in the electroplating industry. A technical comparison between the membrane process and the conventional chemical precipitation process was made.

Conservation of Natural Resources↗

PubMed2001

Class II histone deacetylases: structure, function, and regulation.

Acetylation of histones, as well as non-histone proteins, plays important roles in regulating various cellular processes. Dynamic control of protein acetylation levels in vivo occurs through the opposing actions of histone acetyltransferases and histone deacetylases (HDACs). In the past few years, distinct classes of HDACs have been identified in mammalian cells. Class I members, such as HDAC1, HDAC2, HDAC3, and HDAC8, are well-known enzymatic transcriptional corepressors homologous to yeast Rpd3. Class II members, including HDAC4, HDAC5, HDAC6, HDAC7, and HDAC9, possess domains similar to the deacetylase domain of yeast Hdal. HDAC4, HDAC5, and HDAC7 function as transcriptional corepressors that interact with the MEF2 transcription factors and the N-CoR, BCoR, and CtBP corepressors. Intriguingly, HDAC4, HDAC5, and probably HDAC7 are regulated through subcellular compartmentalization controlled by site-specific phosphorylation and binding of 14-3-3 proteins; the regulation of these HDACs is thus directly linked to cellular signaling networks. Both HDAC6 and HDAC9 possess unique structural modules, so they may have special biological functions. Comprehension of the structure, function, and regulation of class II deacetylases is important for elucidating how acetylation regulates functions of histones and other proteins in vivo.

14-3-3 Proteins↗

PubMed2001

[Aneurysmal model induced by elastase].

OBJECTIVE: To induce the aneurysms by corrosion of aneurysmal wall with elastase, imitating clinical intracranial aneurysms patho-morhologically. METHODS: The elastase-corroded arterial segments were transplanted onto lateral walls of carotid arteries. Follow-up and pathological examination of the aneurysms were made at two weeks and one month after construction. RESULTS: The aneurysms formed by the transplantation of elastase-corroded arterial segments were found persistent or enlarge a little within one month. The aneurysms were purplish red and easy to rupture when exposed. The walls were deprived of elastic layer, and constructed by thin connective tissue. CONCLUSIONS: The aneurysms made by transplanting elastase-corroded arterial segments are simple to built, while morphological and pathological characteristics are demonstrated good clinical mimicry, we believe our aneurysm model may well substitute the most popularly used aneurysms made of venous pouches.

Aneurysm↗

PubMed2000

Histone deacetylase 4 associates with extracellular signal-regulated kinases 1 and 2, and its cellular localization is regulated by oncogenic Ras.

Histone deacetylase 4 (HDAC4) is a member of a family of enzymes that catalyze the removal of acetyl groups from core histones, resulting in a compact chromatin structure that is generally associated with repressed gene transcription. Protein phosphorylation has been implicated in the regulation of the corepressor activity of the deacetylase. Here we report that serine/threonine kinases are found in association with HDAC4 and phosphorylate HDAC4 in vitro, and HDAC4 is phosphorylated in cells. The extracellular signal-regulated kinases 1 and 2 (ERK1/2), also known as p44(MAPK) and p42(MAPK), respectively, are two of the kinases associated with HDAC4. ERK1/2 are components of the Ras-mitogen-activated protein kinase (MAPK) signal transduction pathway. Activation of the Ras-MAPK pathway by expression of oncogenic Ras or constitutively active MAPK/ERK kinase 1 results in an increased percentage of cells (from approximately 10% to approximately 70%) that express HDAC4 in the nucleus in C2C12 myoblast cells. In cells transfected with oncogenic Ras, nuclear HDAC4 is associated with kinase activity. Our results provide evidence that protein kinase activity is present in a protein complex with HDAC4 and directly links the Ras-MAPK signal transduction pathway to a mechanism for chromatin remodeling (i.e., histone deacetylation).

Animals↗