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1.
J Dev Orig Health Dis ; 2(6): 340-52, 2011 Dec.
Article in English | MEDLINE | ID: mdl-23378890

ABSTRACT

Tobacco smoke has both carcinogenic effects and anti-estrogenic properties and its inconsistent association with breast cancer risk in observational studies may be because of these competing effects across the lifecourse. We conducted a prospective study of prenatal smoke exposure, childhood household smoke exposure, and adult active smoke exposure and mammographic density, a strong intermediate marker of breast cancer risk, in an adult follow-up of existing US birth cohorts. Specifically, we followed up women who were born between 1959 and 1967 and whose mothers participated in either the Collaborative Perinatal Project (Boston and Providence sites) or the Childhood Health and Development Study in California. Of the 1134 women interviewed in adulthood (ranging in age from 39 to 49 years at interview), 79% had a screening mammogram. Cigarette smoking was reported by mothers at the time of their pregnancy; 40% of mothers smoked while pregnant. Women whose mothers smoked during pregnancy had a 3.1% (95% confidence interval (CI) = -6.0%, -0.2%) lower mammographic density than women whose mothers did not smoke during pregnancy. When we further accounted for adult body mass index and adult smoking status, the association remained (ß = -2.7, 95% CI = -5.0, -0.3). When we examined patterns of smoking, prenatal smoke exposure without adult smoke exposure was associated with a 5.6% decrease in mammographic density (ß = -5.6, 95% CI = -9.6, -1.6). Given the strength of mammographic density as an intermediate marker for breast cancer, the inverse associations between mammographic density and smoking patterns across the lifecourse may help explain the complex association between cigarette smoking and breast cancer risk.

2.
Exp Cell Res ; 269(1): 162-9, 2001 Sep 10.
Article in English | MEDLINE | ID: mdl-11525649

ABSTRACT

Oncogenic ras (Val 12-containing)-p21 protein induces oocyte maturation by a pathway that is blocked by peptides from effector domains of ras-p21, i.e., residues 35-47 (that block Val 12-p21-activated raf) and 96-110 and 115-126, which do not affect the ability of insulin-activated cellular p21 to induce maturation. Oncogenic p21 binds directly to jun-N-terminal kinase (JNK), which is blocked by the p21 96-110 and 115-126 peptides. This finding predicts that oncogenic p21, but not insulin, induces maturation by early and sustained activation of JNK. We now directly confirm this prediction by showing that oncogenic p21 induces activating phosphorylation of JNK (JNK-P) and of ERK (MAP kinase) (MAPK-P), whose levels correlate with oocyte maturation. p21 peptides 35-47 and 96-110 block formation of JNK-P and MAPK-P, further confirming this correlation and suggesting, unexpectedly, that raf-MEK-MAPK and JNK-jun pathways strongly interact on the oncogenic p21 pathway. In contrast, insulin activates only low levels of JNK-P, and, surprisingly, we find that insulin induces only low levels of MAPK-P, indicating that insulin and activated normal p21 utilize MAP kinase-independent signal transduction pathways.


Subject(s)
Insulin/metabolism , MAP Kinase Signaling System/physiology , Mitogen-Activated Protein Kinases/metabolism , Oocytes/metabolism , Proto-Oncogene Proteins p21(ras)/metabolism , Sexual Maturation/physiology , Animals , Female , Insulin/pharmacology , JNK Mitogen-Activated Protein Kinases , MAP Kinase Signaling System/drug effects , Mitogen-Activated Protein Kinases/drug effects , Oocytes/cytology , Oocytes/drug effects , Peptide Fragments/pharmacology , Phosphorylation/drug effects , Protein Structure, Tertiary/physiology , Proto-Oncogene Proteins p21(ras)/pharmacology , Sexual Maturation/drug effects , Xenopus laevis
3.
Cancer Chemother Pharmacol ; 48(1): 9-14, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11488531

ABSTRACT

PURPOSE: We have previously found that a synthetic peptide corresponding to ras-p21 residues 96 110 (PNC2) selectively blocks oncogenic (Val 12-containing) ras-p21 protein-induced oocyte maturation. With a view to introducing this peptide into ras-transformed human cells to inhibit their proliferation, we synthesized an inducible plasmid that expressed this peptide sequence. Our purpose was to test this expression system in oocytes to determine if it was capable of causing selective inhibition of oncogenic ras-p21. METHODS: We injected this plasmid and a plasmid expressing a control peptide into oocytes either together with oncogenic p21 or in the presence of insulin (that induces maturation that is dependent on normal cellular ras-p21) in the presence and absence of the inducer isopropylthioglucose (IPTG). RESULTS: Microinjection of this plasmid into oocytes together with Val 12-p21 resulted in complete inhibition of maturation in the presence of inducer. Another plasmid encoding the sequence for the unrelated control peptide, X13, was unable to inhibit Val 12-p21-induced maturation. In contrast, PNC2 plasmid had no effect on the ability of insulin-activated normal cellular or wild-type ras-p21 to induce oocyte maturation, suggesting that it is selective for blocking the mitogenic effects of oncogenic (Val 12) ras p21. CONCLUSION: We conclude that the PNC2 plasmid selectively inhibits oncogenic ras-p21 and may therefore be highly effective in blocking proliferation of ras-induced cancer cells. Also, from the patterns of inhibition, by PNC2 and other ras- and raf-related peptides, of raf- and constitutively activated MEK-induced maturation, we conclude that PNC2 peptide inhibits oncogenic ras p21 downstream of raf.


Subject(s)
MAP Kinase Kinase Kinase 1 , Oncogene Protein p21(ras)/antagonists & inhibitors , Oocytes/physiology , Peptide Fragments/genetics , Plasmids , Amino Acid Sequence , Animals , Female , Insulin/pharmacology , Molecular Sequence Data , Protein Serine-Threonine Kinases/antagonists & inhibitors , Xenopus laevis
4.
Biochem Biophys Res Commun ; 255(2): 502-7, 1999 Feb 16.
Article in English | MEDLINE | ID: mdl-10049738

ABSTRACT

Phospholipase D (PLD) activity is commonly elevated in response to mitogenic signals. We reported previously that although the transformed phenotype induced by v-Src was dependent upon Raf-1, the PLD activity induced by v-Src was independent of Raf-1. This observation suggested to us that Raf would not likely be an activator of PLD. However, upon examination of PLD activity in v-Raf-transformed cells, surprisingly, we found that PLD activity is elevated to levels that were even higher than that observed in v-Src-transformed cells. To characterize the mechanism of v-Raf-induced PLD activity, we examined the dependence of v-Raf-induced PLD activity upon protein kinase C (PKC) the small GTPases Ral and Rho, which have all been implicated in the activation of PLD. The v-Raf-induced PLD activity was inhibited by dominant negative mutants for both Ral and Rho. The dependence upon Ral was particularly surprising since Ral is a downstream target of Ras, which is an upstream activator of Raf. Depleting cells of PKC by long term phorbol ester treatment actually increased PLD activity in v-Raf-transformed cells, indicating that v-Raf-induced PLD activity is not dependent on PKC. These data describe a novel mechanism for PLD activation by v-Raf that is independent of PKC, but dependent upon both Ral and Rho GTPases.


Subject(s)
Cell Transformation, Viral , GTP-Binding Proteins/physiology , Phospholipase D/metabolism , Retroviridae Proteins, Oncogenic/physiology , Rho Factor/physiology , 3T3 Cells , Animals , Cell Line, Transformed , Enzyme Activation , GTP Phosphohydrolases/physiology , Mice , Oncogene Proteins v-raf , Protein Kinase C/metabolism , Signal Transduction/physiology , ral GTP-Binding Proteins
5.
Proc Natl Acad Sci U S A ; 95(7): 3632-7, 1998 Mar 31.
Article in English | MEDLINE | ID: mdl-9520417

ABSTRACT

Activation of phospholipase D1 (PLD1) by Arf has been implicated in vesicle transport and membrane trafficking. PLD1 has also been shown to be associated with the small GTPase RalA, which functions downstream from Ras in a Ras-RalA GTPase cascade that facilitates intracellular signal transduction. Although PLD1 associates directly with RalA, RalA has no effect upon the activity of PLD1. However, PLD1 precipitated from cell lysates with immobilized glutathione S-transferase-RalA fusion protein is active. This suggests the presence of an additional activating factor in the active RalA-PLD1 complexes. Because Arf stimulates PLD1, we looked for the presence of Arf in the active RalA-PLD1 complexes isolated from v-Src- and v-Ras-transformed cell lysates. Low levels of Arf protein were detected in RalA-PLD1 complexes; however, if guanosine 5'-[gamma-thio]triphosphate was added to activate Arf and stimulate translocation to the membrane, high levels of Arf were precipitated by RalA from cell lysates. Interestingly, deletion of 11 amino-terminal amino acids unique to Ral GTPases, which abolished the ability of RalA to precipitate PLD activity, prevented the association between RalA and Arf. Brefeldin A, which inhibits Arf GDP-GTP exchange, inhibited PLD activity in v-Src- and v-Ras-transformed cells but not in the nontransformed cells, suggesting that the association of Arf with RalA is required for the increased PLD activity induced by v-Src and v-Ras. These data implicate Arf in the transduction of intracellular signals activated by v-Src and mediated by the Ras-RalA GTPase cascade. Because both Arf and PLD1 stimulate vesicle formation in the Golgi, these data raise the possibility that vesicle formation and trafficking may play a role in the transduction of intracellular signals.


Subject(s)
GTP-Binding Proteins/metabolism , Phospholipase D/metabolism , 3T3 Cells , ADP-Ribosylation Factors , Animals , Enzyme Activation , Mice , Mice, Inbred BALB C , Phospholipase D/chemistry , Signal Transduction , ral GTP-Binding Proteins
6.
Am J Med Genet ; 22(4): 685-94, 1985 Dec.
Article in English | MEDLINE | ID: mdl-4073121

ABSTRACT

Based on analysis of 15 cases, there appears to be a characteristic facial appearance and pattern of associated malformations that would allow clinical delineation of deletion of the distal bands of 1q. Characteristic manifestations include round face with prominent "cupid's bow" and downturned corners of the mouth, thin vermilion borders of lips, long upper lip with smooth philtrum, short and broad nose, epicanthal folds, apparently low-set ears, micrognathia, microcephaly, abnormal hands and feet, variable cardiac, genital, and other anomalies, moderate to severe mental retardation, and growth retardation. The deletion includes 1q42 or 1q43----qter and was a de novo defect in nine of 15 cases.


Subject(s)
Abnormalities, Multiple/genetics , Chromosome Aberrations/pathology , Chromosomes, Human, 1-3 , Chromosome Aberrations/genetics , Chromosome Deletion , Chromosome Disorders , Humans , Phenotype , Syndrome
8.
J Wildl Dis ; 15(4): 593-6, 1979 Oct.
Article in English | MEDLINE | ID: mdl-230365

ABSTRACT

Skin lesions known as "tattoos", were observed in several captive Atlantic bottlenosed dolphins (tursiops truncatus) maintained at the Naval Ocean Systems Center, San Diego, California. Biopsy of typical lesions and subsequent ultrastructural examination revealed intracytoplasmic particles with poxvirus morphology.


Subject(s)
Dolphins/microbiology , Poxviridae Infections/veterinary , Poxviridae/isolation & purification , Animals , Cicatrix/microbiology , Cicatrix/veterinary , Skin/injuries , Skin/microbiology , Skin/ultrastructure
9.
J Am Vet Med Assoc ; 173(9): 1124-6, 1978 Nov 01.
Article in English | MEDLINE | ID: mdl-738929

ABSTRACT

Skeletal lesions observed during necropsy of a wild mature male dolphin (Delphinus delphis) were consistent with fibrous osteodystrophy when examined microscopically. The lesions were pronounced in the ribs, scapulae, and pelvis, with no apparent skull or vertebral involvement. Whether the cause was nutritional or nonnutritional was not determined.


Subject(s)
Animal Population Groups , Animals, Wild , Dolphins , Fibrous Dysplasia of Bone/veterinary , Animals , Fibrous Dysplasia of Bone/pathology , Male , Ribs/pathology , Scapula/pathology
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