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Biomedical subjects

T Jacks

Publications and source records attributed to T Jacks.

At least 109 records · Page 6Linked to original sources
PubMed1994

DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2.

The roles of p53 as an inducer and Bcl-2 as an inhibitor of apoptotic death were explored in lymphoid cells. Lymphocytes from p53-/- mice were radioresistant, but unexpectedly, cycling T lymphoma cells and mitogenically activated T lymphocytes from these animals underwent apoptosis after irradiation or genotoxic drug treatment. Hence, p53 is not the only mediator of apoptosis provoked by DNA damage. Irradiated p53-/- lymphoblasts expressing Bcl-2 were subject to growth arrest but resisted apoptosis. Their accumulation in G1 as well as G2 is suggestive of a p53-independent DNA-damage G1 checkpoint. Since Bcl-2 increased the clonogenic survival of the irradiated cells, expression of survival genes may pose a greater impediment to genotoxic cancer therapy than loss of p53.

Animals↗
PubMed1994

Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences.

Homozygosity for a mutation in the Rb tumor suppressor gene causes mid-gestation embryonic lethality in the mouse. Using a two-step targeting protocol, we have constructed Rb homozygous mutant mouse embryonic stem cells and used them to create chimeric animals partially composed of Rb-deficient cells. Analysis of these chimeras demonstrates widespread contribution of the mutant cells to adult tissues, including the retina and mature erythrocytes. Despite the presence of large numbers of Rb-deficient cells in most tissues of these mice, they are remarkably normal but do exhibit certain histological defects including cataracts, hyperplasia of the adrenal medulla, and enlarged cells in the cerebellum and the liver. Like animals heterozygous for the Rb mutation, the chimeras develop tumors of the intermediate lobe of the pituitary, and the rate of pituitary tumorigenesis is greatly accelerated.

Adrenal Glands↗
PubMed1994

p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens.

The retinoblastoma tumour-suppressor gene (RB) has been implicated in negative growth regulation, induction of differentiation, and inhibition of cellular transformation. Homozygous inactivation of the Rb gene in the mouse leads to mid-gestational lethality with defects in erythropoiesis and neurogenesis. Here we describe the effects of the Rb-deficient state on the development of the ocular lens. The regional compartmentalization of growth, differentiation and apoptosis in the developing lens provides an ideal system to examine more closely the relationships of these processes in vivo. We demonstrate that loss of Rb function is associated with unchecked proliferation, impaired expression of differentiation markers, and inappropriate apoptosis in lens fibre cells. In addition, we show that ectopic apoptosis in Rb-deficient lenses is dependent on p53, because embryos doubly null for Rb and p53 show a nearly complete suppression of this effect. This developmental system provides a framework for understanding the consequences of the frequent mutation of both RB and p53 in human cancer.

Animals↗
PubMed1994

p53-dependent apoptosis suppresses tumor growth and progression in vivo.

To determine the contribution of p53 loss to tumor progression, we have induced abnormal proliferation in the brain choroid plexus epithelium of transgenic mice using a SV40 T antigen fragment that perturbs pRB family function but does not affect p53 function. Tumors induced by this mutant develop slowly compared with those induced by wild-type T antigen. Suppressed tumor growth is directly attributable to p53 function, since rapid tumor development occurs when the T antigen fragment is expressed in p53-null mice. In p53-heterozygous mice, stochastic loss of the wild-type p53 allele results in the focal emergence of aggressive tumor nodules characteristic of tumor progression. In each case, aggressive tumor development in the absence of p53 function corresponds to a decrease in the level of apoptosis. These results provide in vivo evidence that p53-dependent apoptosis, occurring in response to oncogenic events, is a critical regulator of tumorigenesis.

Animals↗
PubMed1994

p53-dependent G1 arrest involves pRB-related proteins and is disrupted by the human papillomavirus 16 E7 oncoprotein.

The cell cycle regulatory tumor suppressor proteins p53 and pRB are targeted for inactivation by several tumor viruses, including the high-risk types of human papillomaviruses (HPVs) via interactions of the HPV E6 and E7 oncoproteins with p53 and pRB, respectively. p53 plays a central role in a signal transduction pathway that mediates G1 arrest after DNA damage, though the mechanism by which G1 arrest occurs has not been elucidated. The cyclin-associated protein p21waf1/cip1 has recently been shown to be induced by p53 and to inhibit cyclin complex-mediated phosphorylation of pRB in vitro. Thus, we investigated a possible role for pRB in the p53-mediated DNA damage response. After gamma-irradiation, cells expressing wild-type p53 arrested in G1, contained increased levels of WAF1/CIP1 mRNA, and demonstrated accumulation of hypophosphorylated pRB. In contrast, cell lines with abnormal p53 genes or with p53 functionally inactivated by the E6 oncoprotein of HPV16 (a high-risk HPV) failed to arrest in G1, did not elevate WAF1/CIP1 mRNA, and did not accumulate hypophosphorylated pRB. Despite apparently normal elevation of p53 protein and WAF1/CIP1 mRNA after irradiation, cells expressing HPV16 E7 also failed to arrest in G1 and did not accumulate hypophosphorylated pRB. Disruption of RB genes alone did not totally abrogate this G1 arrest. Our results suggest that p53 indirectly regulates phosphorylation of pRB and that pRB and/or other pRB-like molecules that bind to HPV16 E7 participate in the DNA damage-mediated G1 arrest signal. In the process of HPV infection, the HPV E6 and E7 oncoproteins may undermine this cell cycle checkpoint, contributing to the accumulation of genetic alterations during tumorigenesis.

Cell Cycle↗
PubMed1994

Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells.

p53-deficient mouse embryonic fibroblasts were used to establish a direct mechanism of tumor suppression by p53 involving the destruction of oncogene-expressing cells by apoptosis. The absence of p53 enhanced cell growth, appeared sufficient for immortalization, and allowed a single oncogene [adenovirus early region 1A (E1A)] to transform cells to a tumorigenic state. p53 suppressed transformation of E1A-expressing cells by apoptosis. Apoptosis was associated with p53 stabilization and was triggered by environmental signals that normally suppress cell growth. Absence of even a single p53 allele significantly enhanced cell growth and survival. Although abrogation of apoptosis allowed transformation by E1A alone, escape from apoptosis susceptibility was not a prerequisite for tumor growth. Consequently, p53 mutation could enhance the survival of malignant cells expressing oncogenes activated early in tumor progression.

Adenovirus E1A Proteins↗
PubMed1994

Tumor spectrum analysis in p53-mutant mice.

BACKGROUND: The p53 tumor suppressor gene is mutated in a large percentage of human malignancies, including tumors of the colon, breast, lung and brain. Individuals who inherit one mutant allele of p53 are susceptible to a wide range of tumor types. The gene encodes a transcriptional regulator that may function in the cellular response to DNA damage. The construction of mouse strains carrying germline mutations of p53 facilitates analysis of the function of p53 in normal cells and tumorigenesis. RESULTS: In order to study the effects of p53 mutation in vivo, we have constructed a mouse strain carrying a germline disruption of the gene. This mutation removes approximately 40% of the coding capacity of p53 and completely eliminates synthesis of p53 protein. As observed previously for a different germline mutation of p53, animals homozygous for this p53 deletion mutation are viable but highly predisposed to malignancy. Heterozygous animals also have an increased cancer risk, although the distribution of tumor types in these animals differs from that in homozygous mutants. In most cases, tumorigenesis in heterozygous animals is accompanied by loss of the wild-type p53 allele. CONCLUSION: We reaffirm that p53 function is not required for normal mouse development and conclude that p53 status can strongly influence tumor latency and tissue distribution.

Alleles↗
PubMed1994

Tumour predisposition in mice heterozygous for a targeted mutation in Nf1.

Human neurofibromatosis type 1 is a dominant disease caused by the inheritance of a mutant allele of the NF1 gene. In order to study NF1 function, we have constructed a mouse strain carrying a germline mutation in the murine homologue. Heterozygous animals do not exhibit the classical symptoms of the human disease, but are highly predisposed to the formation of various tumour types, notably phaeochomocytoma, a tumour of the neural crest-derived adrenal medulla, and myeloid leukaemia, both of which occur with increased frequency in human NF1 patients. The wild-type Nf1 allele is lost in approximately half of the tumours from heterozygous animals. In addition, homozygosity for the Nf1 mutation leads to abnormal cardiac development and mid-gestational embryonic lethality.

Adrenal Gland Neoplasms↗
PubMed1994

Cooperative tumorigenic effects of germline mutations in Rb and p53.

The tumour suppressor genes Rb and p53 are mutated in several types of human cancer, and many tumour types carry mutations in both genes. To study how these genes normally function, we and others have created mouse strains with Rb and p53 mutations. Here we describe the phenotypic effects of combined germline mutations in these two tumour suppressor genes. Mice mutant for both genes have reduced viability and exhibit novel pathology including pinealoblastomas, islet cell tumours, bronchial epithelial hyperplasia and retinal dysplasia. These data indicate that mutations in Rb and p53 can cooperate in the transformation of certain cell types in the mouse.

Adenoma, Islet Cell↗
PubMed1994

Efficacy and specificity of L-692,429, a novel nonpeptidyl growth hormone secretagogue, in beagles.

L-692,429 is a substituted benzolactam that has recently been shown to stimulate GH secretion from rat pituitary cells in vitro with an ED50 of 60 nM. In the current studies, we evaluated the efficacy and specificity of L-692,429 as a GH secretagogue in beagles. L-692,429 at 0.1, 0.25, or 1.0 mg/kg or saline vehicle was administered iv to four male and four female beagles in a balanced cross-over design. Blood samples were collected up to 75 min posttreatment, and serum was assayed for GH, cortisol, PRL, and LH. Mean peak serum GH levels were significantly increased (P < 0.05) by L-692,429 to 13 +/- 2 (mean +/- SEM) ng/ml (0.1 mg/kg), 39 +/- 6 ng/ml (0.25 mg/kg), or 71 +/- 11 ng/ml (1.0 mg/kg) over the saline control value of 3.6 +/- 0.6 ng/ml. Mean peak GH levels occurred at 15 min and had returned to near-baseline levels by 75 min. There was no difference in response between sexes. Mean peak cortisol levels were significantly increased (P < 0.05) by 2.2-, 2.7-, and 3.1-fold above control levels (3.0 +/- 0.2 micrograms/dl) at 25-35 min and returned to near-baseline levels by 75 min. PRL was slightly decreased after L-692,429 treatment, whereas LH was not affected. In a second study, three groups of three male beagles each were administered 5.0 mg/kg L-692,429, iv; iv saline, or 2.2 U/kg ACTH, im. Blood was collected for 8 h posttreatment and assayed for GH, cortisol, ACTH, aldosterone, PRL, insulin, T3, and T4. L-692,429 administration significantly increased (P < 0.05) GH over the control level (6.0 +/- 3.6 ng/ml) to 133 +/- 14 ng/ml by 15 min, with a return to pretreatment levels by 120 min. Cortisol levels were significantly increased (P < 0.05) by 2.0-fold (L-692,429) or 2.9-fold (ACTH) over the saline control peak concentration of 5.6 +/- 1.6 micrograms/dl and were associated with concurrent increases in ACTH levels of 1.2-fold (L-692,429) or 2.1-fold (ACTH) over the saline control peak concentration of 67 +/- 20 pmol/L. Aldosterone, PRL, T3, and T4 were not significantly affected after L-692,429 administration; however, ACTH treatment significantly increased aldosterone (P < 0.05). These data demonstrate that L-692,429 is a novel nonpeptidyl secretagogue that stimulates a marked, but transient, increase in serum GH levels in the dog.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed1994

Effects of acute and repeated intravenous administration of L-692,585, a novel non-peptidyl growth hormone secretagogue, on plasma growth hormone, IGF-1, ACTH, cortisol, prolactin, insulin, and thyroxine levels in beagles.

L-692,585 is a 2-hydroxypropyl derivative of L-692,429, both novel non-peptidyl growth hormone (GH) secretagogues. The effects of single and repeated intravenous administration of L-692,585 on serum or plasma GH and other hormones in beagles were evaluated. In a balanced 8-dog dose-ranging study, compared to the saline control with a mean (+/- S.E.M.) after-dose serum GH peak of 6.1 +/- 1.3 ng/ml, L-692,585 significantly increased (P < 0.05) peak GH concentrations 4.3-fold (32.5 +/- 7.0 ng/ml) at a dose of 0.005 mg/kg, 7-fold (49.4 +/- 10.6 ng/ml) at a dose of 0.02 mg/kg, and 21-fold (134.3 +/- 29.0 ng/ml) at a dose of 0.10 mg/kg. Total GH release, expressed as area under the curve, showed a similar dose-dependent increase. Peak GH levels were recorded at 5 or 15 min after dosing with the levels returning to near baseline by 90 min. Serum cortisol levels were increased above saline control levels in a dose-dependent manner; however, the increases were modest compared to the GH increases. Based on peak responses and total GH release, L-692,585 was 10- to 20-fold and 2- to 2.5-fold more potent than L-692,429 and the growth hormone releasing peptide, GHRP-6, respectively. When L-692,585 was administered once daily for 14 consecutive days at 0, 0.01 or 0.10 mg/kg to each of 6 dogs, peak plasma GH levels and total GH release on days 1, 8 and 15 significantly increased in a dose-dependent manner, and no desensitization was evident.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Cell proliferation, DNA repair, and p53 function are not required for programmed death of prostatic glandular cells induced by androgen ablation.

Androgen ablation induces programmed death of androgen-dependent prostatic glandular cells, resulting in fragmentation of their genomic DNA and the cells themselves into apoptotic bodies. Twenty percent of prostatic glandular cells undergo programmed death per day between day 2 and 5 after castration. During this same period, < 1% of prostatic glandular cells enter the S phase of the cell cycle, documenting that > 95% of these die in G0. During the programmed death of these G0 glandular cells, a futile DNA repair process is induced secondary to the DNA fragmentation. This futile DNA repair is not required, however, since inhibition of this process by > 90% with an appropriately timed hydroxy-urea dosing regimen had no effect upon the extent of the programmed death of these cells after castration. Likewise, p53 gene expression is not required since the same degree of cell death occurred in prostates and seminal vesicles after castration of wild-type and p53-deficient mice.

Animals↗