The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells.

Wen, D X; Xu, Youfeng; Mais, Dale E.; Goldman, Mark E.; McDonnell, Donald P.

doi:10.1128/mcb.14.12.8356

Cited by 314 publications

(198 citation statements)

References 34 publications

Supporting

Mentioning

181

Contrasting

Unclassified

Order By: Relevance

“…In human breast cancer cells, both isoforms can function as ligand-activated transcriptional regulators of progesterone-responsive target genes; moreover, the PR-A isoform can additionally operate as a repressor of steroid hormone receptor actions. For example, progesterone activated PR-A can modulate estrogen action by preventing ER␣-mediated gene transcriptional activation as indicated by reporter gene expression (28,29). In our studies we have observed a decrease in infanticide among male mice lacking PRs, whereas a recent report by Ogawa et al (30) documented a significant increase in infanticide among male ER␣ knockout (ERKO␣) mice.…”

Section: Resultscontrasting

confidence: 55%

“…PR activation may sustain or suppress activity in neurotransmitter circuitries that have been implicated in parental behaviors, such as those that produce vasopressin (2,25,26) and oxytocin (27). Activated PR may also modulate signaling through other steroid receptor-mediated signaling pathways, such as those mediated by estrogen receptors (ERs) (28,29). Progesterone action is mediated by two distinct forms of PR, PR-B, and the N-terminally truncated isoform, PR-A.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Progesterone receptors mediate male aggression toward infants

Schneider

Stone²,

Wynne‐Edwards

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Neuroendocrine mechanisms that mediate male aggression toward infants are poorly understood. Although testosterone is known to enhance aggression in other social contexts, evidence that it modulates aggression toward infants is equivocal. We have found that male progesterone receptor knockout (PRKO) mice exhibit no infanticidal behavior and little aggression toward young. Male PRKO mice also display significantly enhanced parental behaviors. In wild-type mice, blockade of PR induces a behavioral phenotype similar to that of the PRKO males, whereas progesterone exacerbates aggressive tendencies toward infants. Aggressive behaviors directed toward adult males, by contrast, are unaffected by progesterone, PR antagonism, or PR gene deletion. Previously thought to be of diminished importance in male animals, PRs play a critical and specific role in modulating infantdirected behaviors in male mice.A dult male animals display a repertoire of behaviors toward conspecific infants that can include some combination of parental care, indifference, and aggression. Parental care is the least commonly observed of these behaviors among male mammals, though it can predominate in male Djungarian hamsters, Mongolian gerbils, cotton-top tamarins, prairie voles, some strains of mice, and humans. In most strains of laboratory mice, however, indifference or overt aggression toward infants is most common; parental care is usually only observed after careful sensitization of the adult male to pups.The neuroendocrine mechanisms mediating aggressive behavior toward infants remain obscure. Because testosterone (T) has long been known to enhance intermale aggression, the aggression of adult males toward offspring and absence of paternal care have also been considered T-dependent behaviors. High T levels, however, do not necessarily decrease paternal behavior in many species (1, 2) and even promote paternal behavior in the California mouse, Peromyscus californicus (3) via aromatization to estrogen (4). Furthermore, T levels do not correlate with paternal behavior in common laboratory mice (5). In humans, some fathers experience a decrease in T levels immediately after birth of a child (6, 7); however, its association with paternal behaviors is not known.The inconsistency of reported associations between T and infant-directed male behaviors lead us to consider the possibility that this type of male aggression may be governed by neuroendocrine regulatory mechanisms that differ from those controlling intermale aggression. We specifically assessed the possibility that male aggression toward infants may be modulated by progesterone, via the intracellular progesterone receptor (PR). Traditionally viewed as a hormone that controls female reproductive behavior and physiology, recent work has suggested that progesterone may also influence male reproductive behaviors (8) as well as male-specific development of the hypothalamus (9). These findings, together with the observations that progesterone can inhibit parental behaviors in female rodents (10), p...

show abstract

Section: Resultscontrasting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Progesterone receptors mediate male aggression toward infants

Schneider

Stone²,

Wynne‐Edwards

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The human PR exists in two isoforms, a B isoform (PR-B) and an N-terminal truncated A isoform (PR-A), possessing different transcriptional capacities, despite similar hormone-and DNA-binding properties (Kastner et al, 1990;Sartorius et al, 1994;Wen et al, 1994;Richer et al, 2002). T47D cells, here referred to as T47D-WT cells, express both PR-A and -B in an oestrogendependent manner (Keydar et al, 1979;Sutherland et al, 1992).…”

Section: Resultsmentioning

confidence: 99%

Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells

et al. 2006

View full text Add to dashboard Cite

Activation of the type I insulin-like growth factor receptor (IGF-IR) regulates several aspects of the malignant phenotype, including cancer cell proliferation and metastasis. Phosphorylation of adaptor proteins downstream of IGF-IR may couple IGF action to specific cancer phenotypes. In this study, we sought to determine if insulin receptor substrate-1 and -2 (IRS-1 and -2) mediate distinct biological effects in breast cancer cells. Insulin receptor substrate-1 and IRS-2 were expressed in T47D-YA breast cancer cells, which lack IRS-1 and -2 expression, yet retain functional IGF-IR. In the absence of IRS-1 and -2 expression, IGF-IR activation was unable to stimulate proliferation or motility in T47D-YA cells. Expression of IRS-1 resulted in IGF-I-stimulated proliferation, but did not affect motility. In contrast, expression of IRS-2 enhanced IGF-I-stimulated motility, but did not stimulate proliferation. The aIR-3, an inhibitor of the IGF-IR, was unable to affect these IGF-stimulated phenotypes unless IRS-1 or -2 was expressed. Thus, IGF-IR alone is unable to regulate important breast cancer cell phenotypes. In these cells, IRS proteins are required for and mediate distinct aspects of IGF-IRstimulated behaviour. As multiple agents targeting the IGF-IR are currently in early clinical trials, IRS expression should be considered as a potential biomarker for IGF-IR responsiveness.

show abstract

“…Human PR exists as two isoforms, A and B. Altered ratios of PR isoform expression have been reported to be closely associated with modulations of various progesterone actions, [21][22][23][24] but the precise functions of PRA and PRB have not been clearly characterized. In the great majority of progesterone-responsive cells, PRB is a dominant activator of progesterone-responsive target genes, whereas PRA may inhibit this PRB activity.…”

Section: Discussionmentioning

confidence: 99%

Progesterone Receptor A and B Isoforms in the Human Breast and Its Disorders

Ariga¹,

Suzuki²,

Moriya³

et al. 2001

Japanese Journal of Cancer Research

View full text Add to dashboard Cite

Human progesterone receptor (PR) exists as two isoforms, A and B. These isoforms are encoded by separate mRNAs which are transcribed from two distinct promoters, both of which are under estrogen control.1, 2) PRA and PRB are both expressed in progesterone target tissues at comparable levels. The ratio of PRA:PRB has been suggested to influence the biological actions of progesterone. Therefore, investigating the relative ratio of PR isoforms in progesterone-responsive tissues may provide important insights into the physiology and perhaps pathogenesis relating to progesterone-mediated actions.In human breast cancer cells, PRA over-expression has been reported to be associated with an alteration in adhesive properties.3) Previous studies using immunoblot analysis have demonstrated very high levels of PRA (up to 100 fold higher than PRB) in a subset of human breast tumors.4) However, immunolocalization of PR isoform proteins has not been reported in detail in human breast cancer. Therefore, in this study, we first immunolocalized PRA and PRB in human breast cancer and intraductal epithelial proliferative lesions. We then examined the mRNAs for PRA and PRB in invasive ductal carcinoma cases using reverse transcription-polymerase chain reaction (RT-PCR) analysis. We also examined the correlation between these findings and clinicopathological factors of invasive ductal carcinoma including estrogen receptor (ER) α status, Ki67 labeling index (LI), histological grades, and lymph node status, in order to further characterize the biological significance of these PR isoforms in breast carcinoma. MATERIALS AND METHODSCases Surgical pathology specimens were retrieved from the pathology files of Tohoku University Hospital, Sendai, Kawasaki University Hospital, Kurashiki, and Tohoku Kosai Hospital, Sendai. These specimens included 47 cases of invasive ductal carcinoma (IDC), 40 cases of ductal carcinoma in situ (DCIS), 27 cases of atypical ductal hyperplasia (ADH), and 27 cases of proliferative disease without atypia (PDWA) including moderate and florid hyperplasia of the usual type. Pathological diagnosis was based on the work of Dupont et al. 5) and of Ottesen et al. 6)Classification of DCIS was based on the Consensus Conference on the Classification of Ductal Carcinoma In Situ in 1997. 7) Non-pathological breast tissues were available for examination in 13, 12 and 12 cases of DCIS, ADH and PDWA, respectively. All of these specimens were fixed in

show abstract

The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells.

Cited by 314 publications

References 34 publications

Progesterone receptors mediate male aggression toward infants

Progesterone receptors mediate male aggression toward infants

Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells

Progesterone Receptor A and B Isoforms in the Human Breast and Its Disorders

Contact Info

Product

Resources

About