Differential regulation of human progesterone receptor A and B form-mediated trans-activation by phosphorylation.

Kazmi, Syed M.I.; Visconti, Vito; Plante, Richard K.; Ishaque, Adiba; Lau, C. Geoffrey

doi:10.1210/endo.133.3.8365365

Cited by 29 publications

(15 citation statements)

References 34 publications

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“…In this study we have shown that treatment of breast cancer cells with HPR induced a marked dephosphorylation of pRb that involved the consensus residues for Cdk4 (Ser 780 and Ser 795 ) and Cdk2 (Ser 621 and Thr 821 ) relevant for the growth suppressive function of pRb (Connell-Crowley et al, 1997;Knudsen and Wang, 1997;Taya, 1997). Our results, however, are in contrast with another study (Kazmi et al, 1996) showing a marked elevation of pRb levels, rather than phosphorylation changes, in HPRtreated MCF7 cells. The reason for this discrepancy is unclear, given that our data have been observed even under the same estrogen-free culture conditions indicated by these authors.…”

Section: Discussioncontrasting

confidence: 99%

“…Hyper-and hypo-phosphorylated pRb are indicated by the upper and lower bars, respectively 1993; Mariotti et al, 1994;Pienta et al, 1996). Alike other retinoids, HPR can activate the nuclear retinoic acid receptors, and in particular RAR-g and RAR-b, but not RAR-a (Fanjul et al, 1996;Kazmi et al, 1996). However, HPR can elicit retinoid receptordependent and -independent responses (Delia et al, 1997a), both potentially accounting for its biological and therapeutic activity.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, while apoptosis by HPR appears receptor-independent (Delia et al, 1993;Kitareewan et al, 1999), and actually correlates with the ability of HPR to elicit intracellular free radicals and acidi®cation (Delia et al, 1997a;Angoli et al, 1996;Maurer et al, 1999;Suzuki et al, 1999), transcriptional regulation of target genes (e.g. AP1) is retinoid-receptor dependent, according to data showing that HPR selectively activates the transcription by RAR-g, to a less extent by RAR-b, but not by RAR-a (Fanjul et al, 1996;Kazmi et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, the tumor suppressor retinoblastoma protein pRb, a central regulator of the G1/S phase transition (Weinberg, 1995), was found highly upregulated in HPR-treated breast cancer cells (Kazmi et al, 1996), suggesting a link between the antiproliferative activity of the retinoid and pRb regulation. To further verify this issue, and to determine the role of G1 cyclin-dependent kinases (Cdks) that phosphorylate pRb, we examined the expression and activity of these proteins in HPR-treated human breast carcinoma cell lines.…”

Section: Introductionmentioning

confidence: 99%

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pRb and Cdk regulation by N-(4-hydroxyphenyl)retinamide

et al. 2000

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The cancer chemopreventive synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) can inhibit the growth and induce apoptosis of tumor cells. In this study we analysed the growth suppressive e ect of HPR on human breast cancer cell lines in vitro and the role of the retinoblastoma protein (pRb) in this response. Treatment of MCF7, T47D and SKBR3 for 24 ± 48 h with 3 mM HPR, a concentration attainable in vivo, resulted in growth inhibition and marked dephosphorylation of pRb involving Ser 612 , Thr 821 , Ser 795 and Ser 780 , target residues for cyclin-dependent kinase 2 (Cdk2) the former two, and Cdk4 the latter two. Interestingly, this dephosphorylation of pRb occurred in S-G2-M phase cells, as revealed by experiments on cells fractionated by FACS according to the cell cycle phase, hence suggesting that the retinoid interferes with the regulation of pRb phosphorylation. The in vitro phosphorylation of a GST-pRb recombinant substrate by Cdk2 immunocomplexes from MCF7, T47D and SKBR3 was markedly suppressed after HPR treatment, whereas that by Cdk4 complexes was suppressed in T47D and SKBR3 but not in MCF7. The steady-state levels of Cdk2, Cdk4 and Cyclin A proteins were una ected by HPR, while those of Cyclin D1 were signi®cantly reduced in all three cell lines. Interestingly, Cyclin D1 downregulation by HPR correlated with transcriptional repression, but not with enhanced proteolysis of Cyclin D1 typically elicited by other retinoids. Collectively, our data suggest that the antiproliferative activity of HPR arises from its capacity to maintain pRb in a de-phosphorylated growthsuppressive status in S-G2/M, possibly through Cyclin D1 downregulation and inhibition of pRb-targeting Cdks.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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pRb and Cdk regulation by N-(4-hydroxyphenyl)retinamide

et al. 2000

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“…Unlike ATRA, 4-HPR induces its apoptotic effects mainly via retinoid receptor-independent mechanisms (Sheikh et al, 1995;Fanjul et al, 1996;Kazmi et al, 1996). We have recently reported that the production of nitric oxide (NO) is vital for 4-HPR to induce apoptosis in breast cancer cells (Simeone et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production

et al. 2003

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The retinoid N-(4-hydroxyphenyl)retinamide (4-HPR also known as fenretinide) is a potent inducer of apoptosis in breast cancer cells. We observed a 4.5-fold reduction in 4-HPR-mediated apoptosis in MCF-7 breast cancer cells transfected with HER2/neu (MCF-7/HER2) as compared with the parental MCF-7 (MCF-7/WT) cells. Blocking HER2/neu with trastuzumab (Herceptin TM ) led to a sixfold increase in 4-HPR-induced apoptosis in HER2/neuoverexpressing cells. These data indicate that HER2/neu reduces the sensitivity of breast cancer cells to 4-HPR. We showed previously that nitric oxide (NO) is essential for 4-HPR to induce apoptosis in breast cancer cells. The inhibitory effects of the 4-HPR and trastuzumab combination correlated with the amount of NO produced in HER2/neu-overexpressing cells. When a NO synthase (NOS) inhibitor was used to block NO production, decreased apoptosis by the 4-HPR and trastuzumab combination was observed. Furthermore, 4-HPRmediated NOSII expression was lower in MCF-7/HER2 than MCF-7/WT cells, but was increased by trastuzumab in HER2/neu-overexpressing cells. Here we report the novel findings that HER2/neu reduces the ability of 4-HPR to induce apoptosis in breast cancer cells, and that one mechanism by which HER2/neu increases the resistance of breast cancer cells to 4-HPR is by decreasing NOSII-mediated NO production.

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Suppression of NFκB activation and NFκB‐dependent gene expression by tepoxalin, a dual inhibitor of cyclooxygenase and 5‐lipoxygenase

Kazmi¹,

Plante²,

Visconti³

et al. 1995

J of Cellular Biochemistry

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Tepoxalin, a dual inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5LO) with cytokine modifying activity, is also a potent inhibitor of the transcription factor, nuclear factor kappa B (NF kappa B). NF kappa B is a pleiotropic activator that is involved in the regulation of many genes whose products participate in immune or inflammatory responses. Tepoxalin inhibited in a dose related manner NF kappa B activation by PMA + ionomycin or H2O2 in Jurkat and HeLa cells. TNF-alpha-induced NF kappa B was also inhibited by tepoxalin in HeLa cells, while relatively less marked inhibition was observed in Jurkat cells. Activation of NF kappa B in several monocytic cell lines was also suppressed by tepoxalin. However AP-1 stimulation under the same conditions was not affected by tepoxalin. Other CO, LO inhibitors such as naproxen or zileuton did not inhibit NF kappa B activities. This inhibitory activity of tepoxalin was further illustrated by its suppression of NF kappa B regulated genes such as IL-6 in PMA stimulated human PBL and c-myc in IL-2 dependent T cell lines. Tepoxalin also blocked PMA + ionomycin-induced I kappa B degradation in a time-dependent fashion. The possible mechanism of tepoxalin in NF kappa B activation and its potential clinical application are discussed.

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Differential regulation of human progesterone receptor A and B form-mediated trans-activation by phosphorylation.

Cited by 29 publications

References 34 publications

pRb and Cdk regulation by N-(4-hydroxyphenyl)retinamide

pRb and Cdk regulation by N-(4-hydroxyphenyl)retinamide

HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production

Suppression of NFκB activation and NFκB‐dependent gene expression by tepoxalin, a dual inhibitor of cyclooxygenase and 5‐lipoxygenase

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