Mark E. Petersen
University of Utah
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Featured researches published by Mark E. Petersen.
Biochemical Pharmacology | 2013
Noemi Kedei; Andrea Telek; A.M. Michalowski; Matthew B. Kraft; Wei Li; Yam B. Poudel; Arnab Rudra; Mark E. Petersen; Gary E. Keck; Peter M. Blumberg
Bryostatin 1, like the phorbol esters, binds to and activates protein kinase C (PKC) but paradoxically antagonizes many but not all phorbol ester responses. Previously, we have compared patterns of biological response to bryostatin 1, phorbol ester, and the bryostatin 1 derivative Merle 23 in two human cancer cell lines, LNCaP and U937. Bryostatin 1 fails to induce a typical phorbol ester biological response in either cell line, whereas Merle 23 resembles phorbol ester in the U937 cells and bryostatin 1 in the LNCaP cells. Here, we have compared the pattern of their transcriptional response in both cell lines. We examined by qPCR the transcriptional response as a function of dose and time for a series of genes regulated by PKCs. In both cell lines bryostatin 1 differed primarily from phorbol ester in having a shorter duration of transcriptional modulation. This was not due to bryostatin 1 instability, since bryostatin 1 suppressed the phorbol ester response. In both cell lines Merle 23 induced a pattern of transcription largely like that of phorbol ester although with a modest reduction at later times in the LNCaP cells, suggesting that the difference in biological response of the two cell lines to Merle 23 lies downstream of this transcriptional regulation. For a series of bryostatins and analogs which ranged from bryostatin 1-like to phorbol ester-like in activity on the U937 cells, the duration of transcriptional response correlated with the pattern of biological activity, suggesting that this may provide a robust platform for structure activity analysis.
Molecular Carcinogenesis | 2016
Jessica S. Kelsey; Christophe Cataisson; Jin-Qiu Chen; Michelle A. Herrmann; Mark E. Petersen; David O. Baumann; Kevin M. McGowan; Stuart H. Yuspa; Gary E. Keck; Peter M. Blumberg
Bryostatin 1, a complex macrocyclic lactone, is the subject of multiple clinical trials for cancer chemotherapy. Although bryostatin 1 biochemically functions like the classic mouse skin tumor promoter phorbol 12‐myristate 13‐acetate (PMA) to bind to and activate protein kinase C, paradoxically, it fails to induce many of the typical phorbol ester responses, including tumor promotion. Intense synthetic efforts are currently underway to develop simplified bryostatin analogs that preserve the critical functional features of bryostatin 1, including its lack of tumor promoting activity. The degree to which bryostatin analogs maintain the unique pattern of biological behavior of bryostatin 1 depends on the specific cellular system and the specific response. Merle 23 is a significantly simplified bryostatin analog that retains bryostatin like activity only to a limited extent. Here, we show that in mouse epidermal cells the activity of Merle 23 was either similar to bryostatin 1 or intermediate between bryostatin 1 and PMA, depending on the specific parameter examined. We then examined the hyperplastic and tumor promoting activity of Merle 23 on mouse skin. Merle 23 showed substantially reduced hyperplasia and was not tumor promoting at a dose comparable to that for PMA. These results suggest that there may be substantial flexibility in the design of bryostatin analogs that retain its lack of tumor promoting activity.
Journal of Medicinal Chemistry | 2014
Noemi Kedei; Jin Qiu Chen; Michelle A. Herrmann; Andrea Telek; Paul Goldsmith; Mark E. Petersen; Gary E. Keck; Peter M. Blumberg
Protein kinase C (PKC), a validated therapeutic target for cancer chemotherapy, provides a paradigm for assessing structure–activity relations, where ligand binding has multiple consequences for a target. For PKC, ligand binding controls not only PKC activation and multiple phosphorylations but also subcellular localization, affecting subsequent signaling. Using a capillary isoelectric focusing immunoassay system, we could visualize a high resolution isoelectric focusing signature of PKCδ upon stimulation by ligands of the phorbol ester and bryostatin classes. Derivatives that possessed different physicochemical characteristics and induced different patterns of biological response generated different signatures. Consistent with different patterns of PKCδ localization as one factor linked to these different signatures, we found different signatures for activated PKCδ from the nuclear and non-nuclear fractions. We conclude that the capillary isoelectric focusing immunoassay system may provide a window into the integrated consequences of ligand binding and thus afford a powerful platform for compound development.
ChemBioChem | 2018
Thomas J. Cummins; Noemi Kedei; Agnes Czikora; Nancy E. Lewin; Sharon Kirk; Mark E. Petersen; Kevin M. McGowan; Jin-Qiu Chen; Xiaoling Luo; Randall C. Johnson; Sarangan Ravichandran; Peter M. Blumberg; Gary E. Keck
To investigate the cellular distribution of tumor‐promoting vs. non‐tumor‐promoting bryostatin analogues, we synthesized fluorescently labeled variants of two bryostatin derivatives that have previously shown either phorbol ester‐like or bryostatin‐like biological activity in U937 leukemia cells. These new fluorescent analogues both displayed high affinity for protein kinase C (PKC) binding and retained the basic properties of the parent unlabeled compounds in U937 assays. The fluorescent compounds showed similar patterns of intracellular distribution in cells, however; this argues against an existing hypothesis that various patterns of intracellular distribution are responsible for differences in biological activity. Upon further characterization, the fluorescent compounds revealed a slow rate of cellular uptake; correspondingly, they showed reduced activity for cellular responses that were only transient upon treatment with phorbol ester or bryostatin 1.
Antimicrobial Agents and Chemotherapy | 2018
Adam M. Spivak; Racheal A. Nell; Mark E. Petersen; Laura J. Martins; Paul R. Sebahar; Ryan E. Looper; Vicente Planelles
Antiretroviral therapy (ART) does not cure HIV-1 infection due to the persistence of proviruses in long-lived resting T cells. Strategies targeting these latently infected cells will be necessary to eradicate HIV-1 in infected individuals. ABSTRACT Antiretroviral therapy (ART) does not cure HIV-1 infection due to the persistence of proviruses in long-lived resting T cells. Strategies targeting these latently infected cells will be necessary to eradicate HIV-1 in infected individuals. Protein kinase C (PKC) activation is an effective mechanism to reactivate latent proviruses and allows for recognition and clearance of infected cells by the immune system. Several ingenol compounds, naturally occurring PKC agonists, have been described to have potent latency reversal activity. We sought to optimize this activity by synthesizing a library of novel ingenols via esterification of the C-3 hydroxyl group of the ingenol core, which itself is inactive for latency reversal. Newly synthesized ingenol derivatives were evaluated for latency reversal activity, cellular activation, and cytotoxicity alongside commercially available ingenols (ingenol-3,20-dibenzoate, ingenol 3-hexanoate, and ingenol-3-angelate) in HIV latency cell lines and resting CD4+ T cells from aviremic participants. Among the synthetic ingenols that we produced, we identified several compounds that demonstrate high efficacy and represent promising leads as latency reversal agents for HIV-1 eradication.
Cancer Research | 2014
Jessica S. Kelsey; Noemi Kedei; Christophe Cataisson; Mark E. Petersen; Stuart H. Yuspa; Gary E. Keck; Peter M. Blumberg
Protein kinase C (PKC) is differentially regulated in a range of cancers and has become an attractive therapeutic target. A number of natural compounds exist that have been found to regulate PKCs, and the biological responses of each compound can vary. The PKC activator PMA is an established tumor promoter, while others, such as the bryostatins, are non-tumor promoting and have inhibitory effects on the PKC pathway. Because of its effects on the PKC pathway, bryostatin 1 is currently in clinical trials as an anti-cancer agent. Limited availability and the difficulty involved in synthesizing bryostatin 1 make its use as an anti-cancer agent less attractive. Merle 23, a simplified synthetic analog of bryostatin 1, could be an alternative to bryostatin 1 if it acted similarly. Initial investigations of Merle 23 have revealed biological responses both similar to bryostatin 1 and similar to PMA, depending on the system. In U937 leukemia cells Merle 23 acts similar to PMA, and in the LNCaP prostate cancer cell line it behaves more like bryostatin 1. Its behavior in mouse skin is of particular interest, since this is the system in which the tumor promoting activity of PMA and the anti-tumor promoting activity of bryostatin 1 have been characterized. The activity of Merle 23 was compared to PMA and bryostatin 1 in mouse epidermal cells and mouse skin. In mouse primary keratinocytes PMA produces a prolonged morphological response, while the morphological response to bryostatin 1 is transient. The response to Merle 23 is intermediate, but more similar to bryostatin 1. When applied simultaneously, Merle 23, like bryostatin 1, is able to protect the cells from the morphological response induced by PMA. In the PKC pathway, all three compounds promote similar levels of initial PKCδ activation and ERK1/2 phosphorylation. By 24 hrs, however, the responses differ. At high concentrations, bryostatin 1 protects PKCδ from down regulation whereas Merle 23 does not. Bryostatin 1 is also much more potent for down regulation of PKCα, whereas Merle 23 and PMA are similar. The inflammatory response was measured by monitoring the transcript levels of various genes involved in inflammation. PMA induced the largest increase in transcript levels, while Merle 23 was more similar to bryostatin 1. Short-term in vivo analysis reveals no epidermal thickening in response to low doses of Merle 23 whereas the corresponding dose of PMA induced significant hyperplasia. The in vivo analysis of Merle 23 is ongoing. The results presented suggest that Merle 23 behaves more similarly to bryostatin 1 in the mouse epidermal cells at the level of biological response, raising the possibility that it may likewise be non-promoting. The results emphasize that the structure activity relations responsible for the distinct behavior between PMA and bryostatin 1 are distinct for different cellular systems and different biological endpoints. Citation Format: Jessica Kelsey, Noemi Kedei, Christophe Cataisson, Mark Petersen, Stuart Yuspa, Gary Keck, Peter Blumberg. Bryostatin 1 and the simplified analog Merle 23 have similar and opposing properties on mouse epidermal cells and mouse skin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1642. doi:10.1158/1538-7445.AM2014-1642
Cancer Research | 2013
Jessica S. Kelsey; Noemi Kedei; Christophe Cataisson; Mark E. Petersen; Stuart H. Yuspa; Gary E. Keck; Peter M. Blumberg
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Tumor promoting phorbol esters, such as PMA, are potent activators of the PKC pathway. The bryostatins, marine natural products, activate PKCs similarly to phorbol esters but paradoxically inhibit most phorbol ester responses, including skin tumor promotion. Because of this inhibitory activity on the PKC pathway, bryostatin 1 has been the subject of extensive clinical trials. Serious impediments to clinical development, however, have been the scarcity of natural supplies coupled with great structural complexity, making synthesis problematic. Recent synthetic advances are now yielding simplified structural derivatives. Here, we compare the behavior of the bryostatin derivative Merle 23 with that of bryostatin 1 and phorbol 12-myristate 13-acetate (PMA) in mouse epidermal cells. While having similar binding activity on PKC as does bryostatin 1, Merle 23 behaves like PMA rather than like bryostatin 1 in U937 human leukemia cells but conversely behaves more like bryostatin 1 in the human prostate cancer cell line LNCaP. As a first step in assessing whether Merle 23 possesses or lacks skin tumor promoting activity, its activity in mouse primary keratinocyte cultures was assessed. PMA induces a prominent, prolonged morphological response in keratinocytes. Bryostatin 1 induces a similar initial response, which is however very transient. The morphological response to Merle 23 is more prolonged than for bryostatin 1 but much shorter than for PMA. For initial activation of PKCδ or induction of ERK1/2 phosphorylation, all three ligands show similar activity. By 24 hrs, however, bryostatin 1 is much more potent for down regulation of PKCα, whereas Merle 23 and PMA are similar. For PKCδ, bryostatin 1 at higher concentrations protects PKCδ from down regulation whereas Merle 23 does not. Transcriptional responses of various inflammation genes were monitored by qPCR. PMA causes the greatest increase in transcript levels for all genes investigated. In many cases bryostatin 1 induces a smaller response and the response to Merle 23 generally resembles that of bryostatin 1. While these studies are ongoing, they suggest that Merle 23 largely behaves like bryostatin 1 in the mouse epidermal cells. Our findings emphasize the important role of cellular context in determining the pattern of behavior of Merle 23. An important implication is that different cellular environments reveal different structure activity relations for bryostatin 1-like behavior. Finally, our studies raise the possibility that Merle 23, which is significantly simplified relative to bryostatin 1 in its upper two rings, may be non-promoting, at least in the mouse skin tumor promotion system. Citation Format: Jessica Kelsey, Noemi Kedei, Christophe Cataisson, Mark Petersen, Stuart Yuspa, Gary Keck, Peter Blumberg. Comparison of the activity of the bryostatin derivative Merle 23 with that of bryostatin 1 and phorbol ester in mouse epidermal cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2454. doi:10.1158/1538-7445.AM2013-2454
Cancer Research | 2013
Noemi Kedei; Aleksandra M. Michalowski; Mark E. Petersen; Gary E. Keck; Peter M. Blumberg
Bryostatin 1 (bryo 1) is a promising cancer chemotherapeutic agent with a unique mechanism of action. Whereas bryo 1 binds to and activates protein kinase C (PKC) like the phorbol esters, it paradoxically antagonizes most phorbol ester responses. Previously, we compared the changes in transcription in response to the phorbol ester phorbol 12-myristate 13-acetate (PMA), to bryo 1, and to the synthetic bryo 1 derivative Merle 23 in the human cancer cell lines LNCaP and U937. Bryo1 failed to induce a typical phorbol ester biological response in either cell line, whereas the bryo 1 analog Merle 23 resembled PMA in the U937 cells and bryo 1 in the LNCaP cells. In both cell lines, bryo 1 differed from PMA in inducing a shorter duration of the transcriptional responses for a panel of PKC-regulated genes as quantitated by qPCR. Merle 23, in contrast, induced a pattern very similar to that of PMA. Here, we analyzed by microarray the genome wide transcriptional changes in LNCaP and U937 cells treated with maximally effective doses of PMA, bryo 1 and Merle 23 for 6 and 8 hours, respectively. Several thousand genes were significantly up- or down-regulated by PMA (3131 and 3206), bryo 1 (1569 and 2454) and Merle 23 (3533 and 3207) compared to control in LNCaP and U937 cells, respectively. As seen previously for selected genes, the magnitude of the changes was much greater for LNCaP cells than for U937 cells. The great majority of the genes followed a pattern in which bryo 1 induced changes similar to PMA but to a significantly smaller extent (3096 and 1610 genes significantly different in LNCaP and U937 cells), whereas Merle 23 was very similar to PMA (only 230 and 30 genes different between them). A detailed qPCR analysis (dose and time courses) of representative outlier genes revealed that the shorter duration of bryo 1 induced response was responsible for the differences between bryo 1 and PMA effect in all cases. The dose response experiments did not reveal a difference in bryo 1 potency linked to any specific pattern of response. Analysis of transcription factors revealed overrepresentation of the same families of transcription factors (13 in the LNCaP cells; 12 in the U937 cells) among the genes differentially regulated by PMA and bryo 1. These included AP2F, E2F, EGRF, KLF, NRF1, SP1F. However, the target genes of the transcription factor families were largely different between the two cell lines. The analysis of 45 signaling pathways using reporter assays identified significant changes in 7 pathways induced both by PMA and bryo 1 at 6 hours. While the analysis of the microarray data is ongoing, we conclude that early turn-off of the induced responses by bryo 1 is the central feature accounting for its difference from PMA in its transcriptional response. Understanding the basis for this transiency of response may reveal a more general strategy for inhibition of PKC pathways. Citation Format: Noemi Kedei, Aleksandra M. Michalowski, Mark E. Petersen, Gary E. Keck, Peter M. Blumberg. Comparison of transcriptional response to phorbol ester, bryostatin 1, and bryostatin analogue in LNCaP and U937 cells provides insight into their differential mechanism. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2101. doi:10.1158/1538-7445.AM2013-2101
Cancer Research | 2012
Noemi Kedei; Andrea Telek; Aleksandra M. Michalowski; Matthew B. Kraft; Wei Li; Yam B. Poudel; Arnab Rudra; Mark E. Petersen; Gary E. Keck; Peter M. Blumberg
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Bryostatin 1 has attracted great interest as a cancer chemotherapeutic agent with a unique mechanism of action. Whereas bryostatin 1 binds to and activates protein kinase C (PKC) like the phorbol esters, it paradoxically antagonizes many but not all phorbol ester responses. We wish to understand its mechanism(s) of action and how the newly emerging synthetic bryostatin analogs functionally resemble or differ from bryostatin 1. Previously, we have compared patterns of biological response to bryostatin 1, the phorbol ester phorbol 12-myristate 13-acetate (PMA), and the synthetic bryostatin 1 derivative Merle 23 in two human cancer cell lines, LNCaP and U937. Bryostatin 1 fails to induce a typical phorbol ester biological response in either cell line, whereas the bryostatin analog Merle 23 resembles PMA in the U937 cells and bryostatin 1 in the LNCaP cells. Here, we have compared patterns of transcriptional response to bryostatin 1, PMA, and Merle 23 in the same two human cancer cell lines. We examined by qPCR the transcriptional response as a function of dose and time for a series of genes highly regulated downstream of protein kinase C. In both cell lines, bryostatin 1 differed from phorbol ester primarily in having a shorter duration of transcriptional modulation. In LNCaP cells bryostatin 1 induced the majority of the genes similarly to PMA at 2 hours but to much lower levels at 6, 12, and 24 hrs. In U937 cells the bryostatin 1 induced response was similar to that of PMA at 2 hrs but progressively less than that of PMA at 8 hrs and 24 hrs. This was not due to bryostatin 1 instability, since bryostatin 1 suppressed the PMA response at these later times. A notable difference between the two cell lines was in the extent of transcriptional response to PMA, which was much greater in the LNCaP cells than in the U937 cells. In both cell lines Merle 23 induced a pattern of transcription largely like that of PMA rather than bryostatin 1 although with a modest reduction in expression at later times (12 and 24 hrs) in the LNCaP cells. We thus conclude that the difference in biological response of the two cell lines to Merle 23 most likely does not reflect an underlying difference in mechanism but rather reflects the greater absolute magnitude of the differences in response in the LNCaP cells compared to the U937 cells. For a series of bryostatins and synthetic analogues which ranged from bryostatin 1-like to phorbol ester-like in activity on the U937 cells for proliferation and differentiation, the duration of transcriptional response correlated with their pattern of biological activity, suggesting that this may provide a useful endpoint for structure activity analysis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3815. doi:1538-7445.AM2012-3815
Journal of the American Chemical Society | 2016
Michael T. Jacobsen; Mark E. Petersen; Xiang Ye; Mathieu Galibert; George H. Lorimer; Vincent Aucagne; Michael S. Kay