Biomedical subjects

Troy A Baudino

Publications and source records attributed to Troy A Baudino.

8 recordsLinked to original sources

PubMed2006

Cardiac fibroblasts: friend or foe?

Cardiac function is determined by the dynamic interaction of various cell types and the extracellular matrix that composes the heart. This interaction varies with the stage of development and the degree and duration of mechanical, chemical, and electrical signals between the various cell types and the ECM. Understanding how these complex signals interact at the molecular, cellular, and organ levels is critical to understanding the function of the heart under a variety of physiological and pathophysiological conditions. Quantitative approaches, both in vivo and in vitro, are essential to understand the dynamic interaction of mechanical, chemical, and electrical stimuli that govern cardiac function. The fibroblast can thus be a friend in normal function or a foe in pathophysiological conditions.

Animals↗

PubMed2006

Dynamic interactions between myocytes, fibroblasts, and extracellular matrix.

Cardiac function is determined by the coordinated and dynamic interaction of several cell types together with components of the extracellular matrix (ECM). This interaction is regulated by mechanical, chemical, and electrical signals between the cellular and noncellular components of the heart. Recent studies using fluorescence-activated cell sorting indicate that the number of myocytes remains relatively constant during development and disease, whereas the number of fibroblasts and other cell types can change dramatically. Cardiac fibroblasts appear to have different origins at different stages of development and fluctuate in response to a variety of physiological signals. Fibroblasts form a network of cells that are connected to each other via specific cadherins and connexins, to the ECM via integrins, and to myocytes by a variety of receptors, including connexins. Examples of the integration of signals include the role of angiotensin II (Ang II), which stimulates mechanical contraction of fibroblasts, as well as cytokine signaling. Cytokine signaling alters connexin and K(+) channel activation, which in turn is regulated by Ang II, essentially forming a feedback loop. Quantitative changes in mechanical, chemical, and electrical signals that can alter the overall cardiac form and function will be discussed here.

Animals↗

PubMed2005

Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression.

The C-terminal activation domain (C-TAD) of the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha binds the CH1 domains of the related transcriptional coactivators CREB-binding protein (CBP) and p300, an oxygen-regulated interaction thought to be highly essential for hypoxia-responsive transcription. The role of the CH1 domain in vivo is unknown, however. We created mutant mice bearing deletions in the CH1 domains (DeltaCH1) of CBP and p300 that abrogate their interactions with the C-TAD, revealing that the CH1 domains of CBP and p300 are genetically non-redundant and indispensable for C-TAD transactivation function. Surprisingly, the CH1 domain was only required for an average of approximately 35-50% of global HIF-1-responsive gene expression, whereas another HIF transactivation mechanism that is sensitive to the histone deacetylase inhibitor trichostatin A (TSA(S)) accounts for approximately 70%. Both pathways are required for greater than 90% of the response for some target genes. Our findings suggest that a novel functional interaction between the protein acetylases CBP and p300, and deacetylases, is essential for nearly all HIF-responsive transcription.

Amino Acid Sequence↗

PubMed2005

Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation.

Checkpoints that control Myc-mediated proliferation and apoptosis are bypassed during tumorigenesis. Genes encoding polyamine biosynthetic enzymes are overexpressed in B cells from E mu-Myc transgenic mice. Here, we report that disabling one of these Myc targets, Ornithine decarboxylase (Odc), abolishes Myc-induced suppression of the Cdk inhibitors p21(Cip1) and p27(Kip1), thereby impairing Myc's proliferative, but not apoptotic, response. Moreover, lymphoma development was markedly delayed in E mu-Myc;Odc(+/-) transgenic mice and in E mu-Myc mice treated with the Odc inhibitor difluoromethylornithine (DFMO). Strikingly, tumors ultimately arising in E mu-Myc;Odc(+/-) transgenics lacked deletions of Arf, suggesting that targeting Odc forces other routes of transformation. Therefore, Odc is a critical Myc transcription target that regulates checkpoints that guard against tumorigenesis and is an effective target for cancer chemoprevention.

Animals↗

PubMed2004

Mnt loss triggers Myc transcription targets, proliferation, apoptosis, and transformation.

Myc oncoproteins are overexpressed in most cancers and are sufficient to accelerate cell proliferation and provoke transformation. However, in normal cells Myc also triggers apoptosis. All of the effects of Myc require its function as a transcription factor that dimerizes with Max. This complex induces genes containing CACGTG E-boxes, such as Ornithine decarboxylase (Odc), which harbors two of these elements. Here we report that in quiescent cells the Odc E-boxes are occupied by Max and Mnt, a putative Myc antagonist, and that this complex is displaced by Myc-Max complexes in proliferating cells. Knockdown of Mnt expression by stable retroviral RNA interference triggers many targets typical of the "Myc" response and provokes accelerated proliferation and apoptosis. Strikingly, these effects of Mnt knockdown are even manifest in cells lacking c-myc. Moreover, Mnt knockdown is sufficient to transform primary fibroblasts in conjunction with Ras. Therefore, Mnt behaves as a tumor suppressor. These findings support a model where Mnt represses Myc target genes and Myc functions as an oncogene by relieving Mnt-mediated repression.

Animals↗

PubMed2003

Arf tumor suppressor promoter monitors latent oncogenic signals in vivo.

Induction of the Arf tumor suppressor gene by elevated thresholds of mitogenic signals activates a p53-dependent transcriptional response that triggers either growth arrest or apoptosis, thereby countering abnormal cell proliferation. Conversely, Arf inactivation is associated with tumor development. Expression of Arf in tissues of adult mice is difficult to detect, possibly because its induction leads to the arrest or elimination of incipient tumor cells. We replaced coding sequences of exon 1beta of the mouse cellular Arf gene with a cDNA encoding GFP, thereby producing Arf-null animals in which GFP expression is driven by the intact Arf promoter. The Arf promoter was induced in several biologic settings previously shown to elicit mouse p19Arf expression. Inactivation of Arf in this manner led to the outgrowth of tumor cells expressing GFP, thereby providing direct evidence that the Arf promoter monitors latent oncogenic signals in vivo.

Animals↗

PubMed2003

Myc-mediated proliferation and lymphomagenesis, but not apoptosis, are compromised by E2f1 loss.

Myc and E2f1 promote cell cycle progression, but overexpression of either can trigger p53-dependent apoptosis. Mice expressing an Emu-Myc transgene in B lymphocytes develop lymphomas, the majority of which sustain mutations of either the Arf or p53 tumor suppressors. Emu-Myc transgenic mice lacking one or both E2f1 alleles exhibited a slower onset of lymphoma development associated with increased expression of the cyclin-dependent kinase inhibitor p27(Kip1) and a reduced S phase fraction in precancerous B cells. In contrast, Myc-induced apoptosis and the frequency of Arf and p53 mutations in lymphomas were unaffected by E2f1 loss. Therefore, Myc does not require E2f1 to induce Arf, p53, or apoptosis in B cells, but depends upon E2f1 to accelerate cell cycle progression and downregulate p27(Kip1).

ADP-Ribosylation Factor 1↗

PubMed2002

c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression.

c-Myc promotes cell growth and transformation by ill-defined mechanisms. c-myc(-/-) mice die by embryonic day 10.5 (E10.5) with defects in growth and in cardiac and neural development. Here we report that the lethality of c-myc(-/-) embryos is also associated with profound defects in vasculogenesis and primitive erythropoiesis. Furthermore, c-myc(-/-) embryonic stem (ES) and yolk sac cells are compromised in their differentiative and growth potential. These defects are intrinsic to c-Myc, and are in part associated with a requirement for c-Myc for the expression of vascular endothelial growth factor (VEGF), as VEGF can partially rescue these defects. However, c-Myc is also required for the proper expression of other angiogenic factors in ES and yolk sac cells, including angiopoietin-2, and the angiogenic inhibitors thrombospondin-1 and angiopoietin-1. Finally, c-myc(-/-) ES cells are dramatically impaired in their ability to form tumors in immune-compromised mice, and the small tumors that sometimes develop are poorly vascularized. Therefore, c-Myc function is also necessary for the angiogenic switch that is indispensable for the progression and metastasis of tumors. These findings support the model wherein c-Myc promotes cell growth and transformation, as well as vascular and hematopoietic development, by functioning as a master regulator of angiogenic factors.

Angiopoietin-1↗