Regulation of Mammary Lactogenic Differentiation by Singleminded-2s PDF Download
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Author: Elizabeth Wellberg
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Sim2s is a basic helix-loop-helix Per-Arnt-Sim (bHLH-PAS) transcription factor. In Drosophila, the Sim2 homolog, sim, is necessary for cell fate determination during central nervous system (CNS) development. In mammals, both Sim2 isoforms are involved in development of various tissues, including muscle, cartilage, and mammary gland. Loss-of-function studies revealed a role for Sim2s in specifying epithelial cell fate during mammary development and inhibiting growth and invasion of aggressive breast cancer cells. This study determined the role of Sim2s in mammary epithelial cell differentiation. Our hypothesis is that Sim2s is sufficient to promote lactogenic differentiation in vivo, characterized by expression of lactation-specific genes. Two models were used to test this hypothesis: (1) a transgenic mouse, expressing Sim2s under control of the MMTV-LTR, and (2) the mouse mammary epithelial cell line HC11. Together, these models allow analysis of the effect of Sim2s on global mammary gland differentiation and the mechanism through which it accomplishes this in a relatively homogenous population of cells. We determined that precocious expression of Sim2s in vivo is associated with upregulation of a subset of milk protein genes in nulliparous females. During early pregnancy, Sim2s regulation of lactogenic differentiation extended to a larger group of genes. Following pup removal, Sim2s appears to promote survival of alveolar epithelial cells. In vitro, Sim2s expression is necessary for maximal Csn2 expression, as determined by loss-of-function studies. Overexpression of Sim2s is sufficient to enhance prolactin-mediated Csn2 expression. Chromatin immunoprecipitation assays performed in HC11 cells revealed enhanced recruitment of Stat5a and RNA Polymerase II (RNAPII) to the regulatory region of Csn2 in the presence of Sim2s. In addition, Sim2s and RNAPII were found in a complex that was localized to both the promoter and coding region of the Csn2 gene. These studies support the idea that Sim2s is upregulated in a developmental stage-specific manner in the mouse mammary gland to promote the survival and differentiation of alveolar epithelial cells expressing high levels of milk protein genes. Further, Sim2s may regulate the function of a specific subset of alveolar cells by targeting the RNAPII holoenzyme complex to genes expressed during lactogenic differentiation.
Author: Elizabeth Wellberg
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Sim2s is a basic helix-loop-helix Per-Arnt-Sim (bHLH-PAS) transcription factor. In Drosophila, the Sim2 homolog, sim, is necessary for cell fate determination during central nervous system (CNS) development. In mammals, both Sim2 isoforms are involved in development of various tissues, including muscle, cartilage, and mammary gland. Loss-of-function studies revealed a role for Sim2s in specifying epithelial cell fate during mammary development and inhibiting growth and invasion of aggressive breast cancer cells. This study determined the role of Sim2s in mammary epithelial cell differentiation. Our hypothesis is that Sim2s is sufficient to promote lactogenic differentiation in vivo, characterized by expression of lactation-specific genes. Two models were used to test this hypothesis: (1) a transgenic mouse, expressing Sim2s under control of the MMTV-LTR, and (2) the mouse mammary epithelial cell line HC11. Together, these models allow analysis of the effect of Sim2s on global mammary gland differentiation and the mechanism through which it accomplishes this in a relatively homogenous population of cells. We determined that precocious expression of Sim2s in vivo is associated with upregulation of a subset of milk protein genes in nulliparous females. During early pregnancy, Sim2s regulation of lactogenic differentiation extended to a larger group of genes. Following pup removal, Sim2s appears to promote survival of alveolar epithelial cells. In vitro, Sim2s expression is necessary for maximal Csn2 expression, as determined by loss-of-function studies. Overexpression of Sim2s is sufficient to enhance prolactin-mediated Csn2 expression. Chromatin immunoprecipitation assays performed in HC11 cells revealed enhanced recruitment of Stat5a and RNA Polymerase II (RNAPII) to the regulatory region of Csn2 in the presence of Sim2s. In addition, Sim2s and RNAPII were found in a complex that was localized to both the promoter and coding region of the Csn2 gene. These studies support the idea that Sim2s is upregulated in a developmental stage-specific manner in the mouse mammary gland to promote the survival and differentiation of alveolar epithelial cells expressing high levels of milk protein genes. Further, Sim2s may regulate the function of a specific subset of alveolar cells by targeting the RNAPII holoenzyme complex to genes expressed during lactogenic differentiation.
Author: Kelly C Scribner
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Ductal carcinoma in situ (DCIS) has been shown to be a precursor to invasive ductal cancer (IDC). Though the progression of DCIS to IDC is believed to be an important aspect of tumor aggressiveness, prognosis and molecular markers that predict progression are poorly understood. Therefore, determining the mechanisms by which some DCIS progress is critical for future breast cancer diagnostics and treatment. Singleminded-2s (SIM2s) is a member of the bHLH/PAS family of transcription factors and a key regulator of differentiation. SIM2s is highly expressed in mammary epithelial cells and lost in breast cancer. Loss of Sim2s causes aberrant mouse mammary development with features suggestive of malignant transformation, whereas over-expression of Sim2s promotes precocious alveolar differentiation, suggesting that Sim2s is required for establishing and enhancing mammary gland differentiation. We hypothesize that SIM2s expression must be lost in premalignant lesions for breast cancer to develop. We first analyzed Sim2s in the involuting mammary gland, which is a highly tumorpromoting environment. Sim2s is down-regulated during involution, and forced expression delays involution. We then analyzed SIM2s expression in human breast cancer samples and found that SIM2s is lost with progression from DCIS to IDC, and this loss correlates with metastasis. SIM2s expression in DCIS promoted a differentiated phenotype and suppressed genes associated with de-differentiation. Furthermore, loss of SIM2s expression in DCIS xenografts increased metastasis likely due to an increase in hedgehog signaling and matrix metalloproteinase expression. Interestingly, we found metabolic shifts with gain and loss of SIM2s in not only DCIS cells, but also MCF7 and SUM159 cells. SIM2s expression decreased aerobic glycolysis and promoted oxidative phosphorylation through direct upregulation of CDKN1a and senescence. Loss of SIM2s, conversely, promotes mitochondrial dysfunction and induction of the Warburg effect. This is the first time CDKN1a and cellular senescence have been indicated as causative to metabolic shifts within cancer cells. These studies show a new role for SIM2s in metabolic homeostasis, and this regulation is lost during tumorigenesis. These data indicate SIM2s is at the apex where aging, metabolism, and disease meet -- regulating the delicate relationship between the three. The electronic version of this dissertation is accessible from http://hdl.handle.net/1969.1/151007
Author: Traci Galbaugh
Publisher:
ISBN:
Category :
Languages : en
Pages : 97
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Author:
Publisher: ScholarlyEditions
ISBN: 1464920699
Category : Medical
Languages : en
Pages : 1746
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Book Description
Proteins: Advances in Research and Application: 2011 Edition is a ScholarlyEditions™ eBook that delivers timely, authoritative, and comprehensive information about Amino Acids, Peptides, and Proteins. The editors have built Proteins: Advances in Research and Application: 2011 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Amino Acids, Peptides, and Proteins in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Proteins: Advances in Research and Application: 2011 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
Author:
Publisher: ScholarlyEditions
ISBN: 1464990522
Category : Medical
Languages : en
Pages : 5343
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Book Description
Proteins—Advances in Research and Application: 2012 Edition is a ScholarlyEditions™ eBook that delivers timely, authoritative, and comprehensive information about Proteins. The editors have built Proteins—Advances in Research and Application: 2012 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Proteins in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Proteins—Advances in Research and Application: 2012 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
Author: Kenneth E. Maxwell
Publisher: Springer
ISBN: 1489959882
Category : Science
Languages : en
Pages : 319
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Book Description
"The sex imperative - the irresistible impulse to engage in sexual relations - has enabled animals to share their genes and evolve. Maxwell traces the progress of sex from the simple sharing of genes between cells to the elaborate courtship rituals that developed so sperm could merge with egg. In the effort to join sperm and egg, species have developed some astounding and unusual sexual adaptations. As Maxwell vividly describes the sex lives of various creatures, he attests to the resiliency and amazing adaptability of life to its everchanging environment. By focusing on the diversity of animal sexual relationships, Maxwell enables us to question the very basis of sexuality: What is sex? Why did it evolve? How does sexuality and survival shape the social behavior of animals and humans? The sex imperative is indeed the driving force behind Darwin's theory of random variation and natural selection, better known as "survival of the fittest." Maxwell goes so far as to investigate our latest accomplishment in the science of begetting offspring: genetic engineering." "This awe-inspiring and unique work celebrates the power and wonder of life and sexuality of all creatures - including humans. After reading this engrossing and illuminating work, no one will ever think of evolution in the same way."--Jacket
Author: Jose Russo
Publisher: Springer Science & Business Media
ISBN: 1461448840
Category : Medical
Languages : en
Pages : 461
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Book Description
This book will provide the latest advances in molecular and cellular biology for establishing the foundation of a complete understanding of the mechanisms of breast differentiation leading to cancer prevention. The authors are based on the epidemiological evidence indicating that early first full term pregnancy is a protective factor in human against breast cancer and they have used this paradigm and developed experimental systems in both in vivo and in vitro that have demonstrated mechanistically how the differentiation at the organ and cellular level takes place. This knowledge has provided the blueprint for developing better understanding of the basis of cancer prevention. The transcriptoma analysis of the breast of pre and post-menopausal women has established a genomic signature imprinted in the breast that differs according to the reproductive history of the woman showing that early first full term pregnancy reprogram the organ. This reprogramming takes place at the chromatin level by changing the transcriptional process. The modification of the transcriptional control is due to the expression of non coding RNA sequences and posttranscriptional control driven by the splicesome. The plasticity of the genome of the human breast make possible this reprogramming that is not only induced by the physiological process of pregnancy but by the use of hormones that mimic pregnancy without pregnancy. The author have established the basis of clinical trials for prevention and the discovery that short 15aa peptides of the chorionic gonadotropin hormone can be used in human breast cancer prevention based on preclinical and clinical data.
Author: John Desmond Bernal
Publisher:
ISBN:
Category : Biophysics
Languages : en
Pages : 94
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Author: W.E. Blatz
Publisher: University of Toronto Press
ISBN: 1442633816
Category : Psychology
Languages : en
Pages : 214
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Book Description
During his lifetime, W.E. Blatz was so much occupied with the development of the University of Toronto’s Institute of Child Study that he was able to devote little time to writing. This is his first book to appear in twenty-one years, and his first complete exposition of his famous Theory of Security. The Theory of Security is radically different from the theories promulgated by Freudian psychologists. Whereas Freudian personality theory is based on the notion of “unconscious,” an entity that is only indirectly observable, the Theory of Security derives from the observation of the conscious state in all its manifestations. Dr. Blatz thus makes use of both empirical observations and the results of introspection, and, as might be expected, some of his conclusions run counter to those reached in much current psychological discussion. But proof of the forcible influence of the theory and its author may be found in the impressive number of books and articles already published by Dr. Blatz’s associates at the Institute of Child Study, applying the theory to the practical problems of psychological observation and therapy. It is fitting that the man whose work has generated so much fruitful research by others in this field should at last have set down in book form the fundamental principles that guided them.
Author: Rachel Sarah O'Toole
Publisher: University of Pittsburgh Pre
ISBN: 0822977966
Category : History
Languages : en
Pages : 274
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Book Description
Bound Lives chronicles the lived experience of race relations in northern coastal Peru during the colonial era. Rachel Sarah O'Toole examines how Andeans and Africans negotiated and employed casta, and in doing so, constructed these racial categories. Royal and viceregal authorities separated "Indians" from "blacks" by defining each to specific labor demands. Casta categories did the work of race, yet, not all casta categories did the same type of work since Andeans, Africans, and their descendants were bound by their locations within colonialism and slavery. The secular colonial legal system clearly favored indigenous populations. Andeans were afforded greater protections as "threatened" native vassals. Despite this, in the 1640s during the rise of sugar production, Andeans were driven from their assigned colonial towns and communal property by a land privatization program. Andeans did not disappear, however; they worked as artisans, muleteers, and laborers for hire. By the late seventeenth and early eighteenth centuries, Andeans employed their legal status as Indians to defend their prerogatives to political representation that included the policing of Africans. As rural slaves, Africans often found themselves outside the bounds of secular law and subject to the judgments of local slaveholding authorities. Africans therefore developed a rhetoric of valuation within the market and claimed new kinships to protect themselves in disputes with their captors and in slave-trading negotiations. Africans countered slaveholders' claims on their time, overt supervision of their labor, and control of their rest moments by invoking customary practices. Bound Lives offers an entirely new perspective on racial identities in colonial Peru. It highlights the tenuous interactions of colonial authorities, indigenous communities, and enslaved populations and shows how the interplay between colonial law and daily practice shaped the nature of colonialism and slavery.
