Umeå University's logo

umu.sePublications
Change search
Link to record
Permanent link

Direct link
Grundström, Thomas
Publications (10 of 47) Show all publications
Grundström, C. & Grundström, T. (2023). The transcription factor E2A can bind to and cleave single-stranded immunoglobulin heavy chain locus DNA. Molecular Immunology, 153, 51-59
Open this publication in new window or tab >>The transcription factor E2A can bind to and cleave single-stranded immunoglobulin heavy chain locus DNA
2023 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 153, p. 51-59Article in journal (Refereed) Published
Abstract [en]

Class switch recombination (CSR) changes the constant region of the immunoglobulin heavy chain (IgH), and somatic hypermutation (SH) introduces point mutations in the variable regions of the antibody genes. Both these processes that optimize antibody responses of B lymphocytes are initiated by the enzyme Activation Induced cytidine Deaminase (AID). Here we have searched for CSR or SH coupled activities of the transcription factor E2A, since E2A is in a complex with AID and the transcription factors PAX5, ETS1 and IRF4 on key sequences of the Igh locus in B lymphocytes activated to CSR and SH. We report that E2A in contrast to other described transcription factors binds sequence specifically also to single-stranded DNA. The binding of E2A to single-stranded DNA has a strong sequence preference for one strand of a site in the intronic enhancer of the Igh locus. Furthermore, E2A was also found to cleave single-stranded DNA. The sequence profile of substrates cleaved by E2A is coupled to the sequences of substrates and products of AID, suggesting that E2A has a role not only in targeting of AID to switch regions and SH parts of antibody genes but also in cleavage of DNA at these sites.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Class switch recombination, somatic hypermutation, transcription factors, E2A, DNA binding, DNA cleavage
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-201368 (URN)10.1016/j.molimm.2022.11.013 (DOI)000899361800006 ()2-s2.0-85142366831 (Scopus ID)
Funder
Swedish Cancer Society, CAN 2018/547
Available from: 2022-12-01 Created: 2022-12-01 Last updated: 2023-09-05Bibliographically approved
Flodbring Larsson, P., Karlsson, R., Sarwar, M., Miftakhova, R. R., Wang, T., Khaja, A. S., . . . Persson, J. L. (2022). FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer. Molecular Oncology
Open this publication in new window or tab >>FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer
Show others...
2022 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261Article in journal (Refereed) Published
Abstract [en]

Low-affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) is a cell surface protein that belongs to a family of Fc receptors that facilitate the protective function of the immune system against pathogens. However, the role of FcγRIIIa in prostate cancer (PCa) progression remained unknown. In this study, we found that FcγRIIIa expression was present in PCa cells and its level was significantly higher in metastatic lesions than in primary tumors from the PCa cohort (P = 0.006). PCa patients with an elevated level of FcγRIIIa expression had poorer biochemical recurrence (BCR)-free survival compared with those with lower FcγRIIIa expression, suggesting that FcγRIIIa is of clinical importance in PCa. We demonstrated that overexpression of FcγRIIIa increased the proliferative ability of PCa cell line C4-2 cells, which was accompanied by the upregulation of androgen receptor (AR) and phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), which are the key players in controlling PCa progression. Conversely, targeted inhibition of FcγRIIIa via siRNA-mediated knockdown or using its inhibitory antibody suppressed growth of xenograft PC-3 and PC-3M prostate tumors and reduced distant metastasis in xenograft mouse models. We further showed that elevated expression of AR enhanced FcγRIIIa expression, whereas inhibition of AR activity using enzalutamide led to a significant downregulation of FcγRIIIa protein expression. Similarly, inhibition of PIP5K1α decreased FcγRIIIa expression in PCa cells. FcγRIIIa physically interacted with PIP5K1α and AR via formation of protein-protein complexes, suggesting that FcγRIIIa is functionally associated with AR and PIP5K1α in PCa cells. Our study identified FcγRIIIa as an important factor in promoting PCa growth and invasion. Further, the elevated activation of FcγRIII and AR and PIP5K1α pathways may cooperatively promote PCa growth and invasion. Thus, FcγRIIIa may serve as a potential new target for improved treatment of metastatic and castration-resistant PCa.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
AR pathway and antibody-based therapy, FcγRIIIa receptor, PIP5K1α, prostate cancer metastasis, targeted therapy
National Category
Cancer and Oncology
Research subject
Medicine; molecular medicine (genetics and pathology)
Identifiers
urn:nbn:se:umu:diva-192100 (URN)10.1002/1878-0261.13166 (DOI)000745727600001 ()34932854 (PubMedID)2-s2.0-85123504907 (Scopus ID)
Funder
Swedish Cancer Society, 2017-381Swedish Research Council, 2019-01318The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IG2013-5595The Kempe FoundationsCancerforskningsfonden i Norrland
Available from: 2022-02-01 Created: 2022-02-01 Last updated: 2024-03-20Bibliographically approved
Wang, T., Sarwar, M., Whitchurch, J. B., Collins, H. M., Green, T., Semenas, J., . . . Persson, J. L. (2022). PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer. Frontiers in Cell and Developmental Biology, 10, Article ID 798590.
Open this publication in new window or tab >>PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer
Show others...
2022 (English)In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 10, article id 798590Article in journal (Refereed) Published
Abstract [en]

PIP5K1α has emerged as a promising drug target for the treatment of castration-resistant prostate cancer (CRPC), as it acts upstream of the PI3K/AKT signaling pathway to promote prostate cancer (PCa) growth, survival and invasion. However, little is known of the molecular actions of PIP5K1α in this process. Here, we show that siRNA-mediated knockdown of PIP5K1α and blockade of PIP5K1α action using its small molecule inhibitor ISA-2011B suppress growth and invasion of CRPC cells. We demonstrate that targeted deletion of the N-terminal domain of PIP5K1α in CRPC cells results in reduced growth and migratory ability of cancer cells. Further, the xenograft tumors lacking the N-terminal domain of PIP5K1α exhibited reduced tumor growth and aggressiveness in xenograft mice as compared to that of controls. The N-terminal domain of PIP5K1α is required for regulation of mRNA expression and protein stability of PIP5K1α. This suggests that the expression and oncogenic activity of PIP5K1α are in part dependent on its N-terminal domain. We further show that PIP5K1α acts as an upstream regulator of the androgen receptor (AR) and AR target genes including CDK1 and MMP9 that are key factors promoting growth, survival and invasion of PCa cells. ISA-2011B exhibited a significant inhibitory effect on AR target genes including CDK1 and MMP9 in CRPC cells with wild-type PIP5K1α and in CRPC cells lacking the N-terminal domain of PIP5K1α. These results indicate that the growth of PIP5K1α-dependent tumors is in part dependent on the integrity of the N-terminal sequence of this kinase. Our study identifies a novel functional mechanism involving PIP5K1α, confirming that PIP5K1α is an intriguing target for cancer treatment, especially for treatment of CRPC.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2022
Keywords
androgen receptor (AR), castration-resistant prostate cancer (CRPC), cyclin-dependent kinase (CDK), matrix metalloproteinases 9 (MMP9) PIP5K1α, phosphatidylinositol 4-phosphate 5 kinase (PIP5K1α), targeted therapy
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-193614 (URN)10.3389/fcell.2022.798590 (DOI)000780059400001 ()35386201 (PubMedID)2-s2.0-85128078251 (Scopus ID)
Funder
EU, Horizon 2020, 721297Swedish Childhood Cancer Foundation, TJ2015-0097Swedish Cancer Society, CAN-2017-381Swedish Research Council, 2019-01318The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IG2013-5595The Kempe FoundationsCancerforskningsfonden i Norrland
Available from: 2022-04-07 Created: 2022-04-07 Last updated: 2023-05-23Bibliographically approved
Semenas, J., Wang, T., Khaja, A. S., Mahmud, A. K., Simoulis, A., Grundström, T., . . . Persson, J. L. (2021). Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer. Molecular Oncology, 15(4), 968-986
Open this publication in new window or tab >>Targeted inhibition of ERα signaling and PIP5K1α/Akt pathways in castration‐resistant prostate cancer
Show others...
2021 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 15, no 4, p. 968-986Article in journal (Refereed) Published
Abstract [en]

Selective ERα modulator, tamoxifen, is well tolerated in a heavily pretreated castration‐resistant prostate cancer (PCa) patient cohort. However, its targeted gene network and whether expression of intratumor ERα due to androgen‐deprivation therapy (ADT) may play a role in PCa progression is unknown. In this study, we examined the inhibitory effect of tamoxifen on castration‐resistant PCa in vitro and in vivo. We found that tamoxifen is a potent compound that induced a high degree of apoptosis and significantly suppressed growth of xenograft tumors in mice, at a degree comparable to ISA‐2011B, an inhibitor of PIP5K1α that acts upstream of PI3K/AKT survival signaling pathway. Moreover, depletion of tumor‐associated macrophages using clodronate in combination with tamoxifen increased inhibitory effect of tamoxifen on aggressive prostate tumors. We showed that both tamoxifen and ISA‐2011B exert their on‐target effects on prostate cancer cells by targeting cyclin D1 and PIP5K1α/AKT network and the interlinked estrogen signaling. Combination treatment using tamoxifen together with ISA‐2011B resulted in tumor regression and had superior inhibitory effect compared with that of tamoxifen or ISA‐2011B alone. We have identified sets of genes that are specifically targeted by tamoxifen, ISA‐2011B or combination of both agents by RNA‐seq. We discovered that alterations in unique gene signatures, in particular estrogen‐related marker genes are associated with poor patient disease‐free survival. We further showed that ERα interacted with PIP5K1α through formation of protein complexes in the nucleus, suggesting a functional link. Our finding is the first to suggest a new therapeutic potential to inhibit or utilize the mechanisms related to ERα, PIP5K1α/AKT network and MMP9/VEGF signaling axis, providing a strategy to treat castration‐resistant ER‐positive subtype of prostate cancer tumors with metastatic potential.

Place, publisher, year, edition, pages
John Wiley & Sons, 2021
Keywords
Castration-resistant prostate cancer, PI3K/AKT pathway and tamoxifen, PIP5K1α, estrogen receptor, targeted therapy
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-177666 (URN)10.1002/1878-0261.12873 (DOI)000599152900001 ()33275817 (PubMedID)2-s2.0-85097594187 (Scopus ID)
Funder
Swedish Cancer Society, CAN-2017-381Swedish Research Council, 2019-01318
Available from: 2020-12-16 Created: 2020-12-16 Last updated: 2022-12-15Bibliographically approved
Karlsson, R., Larsson, P., Miftakhova, R. R., Khaja, A. S., Sarwar, M., Semenas, J., . . . Persson, J. L. (2020). Establishment of Prostate Tumor Growth and Metastasis Is Supported by Bone Marrow Cells and Is Mediated by PIP5K1α Lipid Kinase. Cancers, 12(9), Article ID 2719.
Open this publication in new window or tab >>Establishment of Prostate Tumor Growth and Metastasis Is Supported by Bone Marrow Cells and Is Mediated by PIP5K1α Lipid Kinase
Show others...
2020 (English)In: Cancers, ISSN 2072-6694, Vol. 12, no 9, article id 2719Article in journal (Refereed) Published
Abstract [en]

Cancer cells facilitate growth and metastasis by using multiple signals from the cancer-associated microenvironment. However, it remains poorly understood whether prostate cancer (PCa) cells may recruit and utilize bone marrow cells for their growth and survival. Furthermore, the regulatory mechanisms underlying interactions between PCa cells and bone marrow cells are obscure. In this study, we isolated bone marrow cells that mainly constituted populations that were positive for CD11b and Gr1 antigens from xenograft PC-3 tumor tissues from athymic nu/nu mice. We found that the tumor-infiltrated cells alone were unable to form tumor spheroids, even with increased amounts and time. By contrast, the tumor-infiltrated cells together with PCa cells formed large numbers of tumor spheroids compared with PCa cells alone. We further utilized xenograft athymic nu/nu mice bearing bone metastatic lesions. We demonstrated that PCa cells were unable to survive and give rise to colony-forming units (CFUs) in media that were used for hematopoietic cell colony-formation unit (CFU) assays. By contrast, PC-3M cells survived when bone marrow cells were present and gave rise to CFUs. Our results showed that PCa cells required bone marrow cells to support their growth and survival and establish bone metastasis in the host environment. We showed that PCa cells that were treated with either siRNA for PIP5K1α or its specific inhibitor, ISA-2011B, were unable to survive and produce tumor spheroids, together with bone marrow cells. Given that the elevated expression of PIP5K1α was specific for PCa cells and was associated with the induced expression of VEGF receptor 2 in PCa cells, our findings suggest that cancer cells may utilize PIP5K1α-mediated receptor signaling to recruit growth factors and ligands from the bone marrow-derived cells. Taken together, our study suggests a new mechanism that enables PCa cells to gain proliferative and invasive advantages within their associated host microenvironment. Therapeutic interventions using PIP5K1α inhibitors may not only inhibit tumor invasion and metastasis but also enhance the host immune system.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
prostate cancer metastasis, bone marrow cells, PIP5K1α, therapeutic interventions
National Category
Clinical Laboratory Medicine Cancer and Oncology
Research subject
biomedical laboratory science
Identifiers
urn:nbn:se:umu:diva-175507 (URN)10.3390/cancers12092719 (DOI)000582024400001 ()32971916 (PubMedID)2-s2.0-85091205597 (Scopus ID)
Projects
tumor microenvironment
Funder
Swedish Cancer Society, CAN2017/381Swedish Research CouncilCancerforskningsfonden i Norrland
Available from: 2020-09-30 Created: 2020-09-30 Last updated: 2023-03-24Bibliographically approved
Grundström, C., Kumar, A., Priya, A., Negi, N. & Grundström, T. (2018). ETS1 and PAX5 transcription factors recruit AID to Igh DNA. European Journal of Immunology, 48(10), 1687-1697
Open this publication in new window or tab >>ETS1 and PAX5 transcription factors recruit AID to Igh DNA
Show others...
2018 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 48, no 10, p. 1687-1697Article in journal (Refereed) Published
Abstract [en]

B lymphocytes optimize antibody responses by class switch recombination (CSR), which changes the expressed constant region exon of the immunoglobulin heavy chain (IgH), and by somatic hypermutation (SH) that introduces point mutations in the variable regions of the antibody genes. Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates both these antibody diversification processes by deaminating cytosine to uracil. Here we asked the question if transcription factors can mediate the specific targeting of the antibody diversification by recruiting AID. We have recently reported that AID is together with the transcription factors E2A, PAX5 and IRF4 in a complex on key sequences of the Igh locus. Here we report that also ETS1 is together with AID in this complex on key sequences of the Igh locus in splenic B cells of mice. Furthermore, we show that both ETS1 and PAX5 can directly recruit AID to DNA sequences from the Igh locus with the specific binding site for the transcription factor. Taken together, our findings support the notion of a targeting mechanism for the selective diversification of antibody genes with limited genome wide mutagenesis by recruitment of AID by PAX5 and ETS1 in a transcription factor complex.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018
Keywords
Activation-induced cytidine deaminase, Class switch recombination, Protein interactions, Somatic hypermutation, Transcription factors
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-152886 (URN)10.1002/eji.201847625 (DOI)000446431600008 ()30089192 (PubMedID)2-s2.0-85052786100 (Scopus ID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2018-10-31 Created: 2018-10-31 Last updated: 2023-03-24Bibliographically approved
Kumar, A., Priya, A., Ahmed, T., Grundström, C., Negi, N. & Grundström, T. (2018). Regulation of the DNA Repair Complex during Somatic Hypermutation and Class-Switch Recombination. Journal of Immunology, 200(12), 4146-4156
Open this publication in new window or tab >>Regulation of the DNA Repair Complex during Somatic Hypermutation and Class-Switch Recombination
Show others...
2018 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 200, no 12, p. 4146-4156Article in journal (Refereed) Published
Abstract [en]

B lymphocytes optimize Ab responses by somatic hypermutation (SH), which introduces pointmutations in the variable regions of the Ab genes and by class-switch recombination (CSR), which changes the expressed C region exon of the IgH. These Ab diversification processes are initiated by the deaminating enzyme activation-induced cytidine deaminase followed by many DNA repair enzymes, ultimately leading to deletions and a high mutation rate in the Ab genes, whereas DNA lesions made by activation-induced cytidine deaminase are repaired with low error rate on most other genes. This indicates an advanced regulation of DNA repair. In this study, we show that initiation of Ab diversification in B lymphocytes of mouse spleen leads to formation of a complex between many proteins in DNA repair. We show also thatBCR activation, which signals the end of successful SH, reduces interactions between some proteins in the complex and increases other interactions in the complex with varying kinetics. Furthermore, we show increased localization of SH-and CSR-coupled proteins on switch regions of the Igh locus upon initiation of SH/CSR and differential changes in the localization upon BCR signaling, which terminates SH. These findings provide early evidence for a DNA repair complex or complexes that may be of functional significance for carrying out essential roles in SH and/or CSR in B cells.

Place, publisher, year, edition, pages
American Association of Immunologists, 2018
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-151570 (URN)10.4049/jimmunol.1701586 (DOI)000442386300029 ()29728513 (PubMedID)2-s2.0-85048406093 (Scopus ID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2018-09-10 Created: 2018-09-10 Last updated: 2023-03-24Bibliographically approved
Hauser, J., Grundström, C., Kumar, R. & Grundström, T. (2016). Regulated localization of an AID complex with E2A, PAX5 and IRF4 at the Igh locus. Molecular Immunology, 80, 78-90
Open this publication in new window or tab >>Regulated localization of an AID complex with E2A, PAX5 and IRF4 at the Igh locus
2016 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 80, p. 78-90Article in journal (Refereed) Published
Abstract [en]

Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates somatic hypermutation (SH) and class switch recombination (CSR) by deaminating cytosine to uracil. The targeting of AID and therefore SH and CSR to Ig genes is a central process of the immune system, but the trans-acting factors mediating the specific targeting have remained elusive. Here we show that defective calmodulin inhibition of the transcription factor E2A after activation of the B cell receptor (BCR) leads to reduced BCR, IL4 plus CD40 ligand stimulated CSR to IgE and instead CSR to other Ig classes. AID that initiates CSR is shown to be in a complex with the transcription factors E2A, PAX5 and IRF4 on key sequences of the Igh locus. Calmodulin shows proximity with each of them after BCR stimulation. BCR signaling reduces binding of the proteins to some of the target sites on the Igh locus, and calmodulin resistance of E2A blocks these reductions. AID binds directly to the bHLH domain of E2A and to the PD domain of PAX5. E2A, AID, PAX5 and IRF4 are components of a CSR complex that is redistributed on the Igh locus by BCR signaling through calmodulin binding.

Keywords
Class switch recombination, Antibodies, Activation-induced cytidine deaminase, Transcription factors, E2A, Calmodulin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-130546 (URN)10.1016/j.molimm.2016.10.014 (DOI)000395847100010 ()2-s2.0-84994651161 (Scopus ID)
Available from: 2017-01-23 Created: 2017-01-23 Last updated: 2018-06-09Bibliographically approved
Grundström, T., Hauser, J., Grundström, C., Kumar, A., Priya, A. & Kumar, R. (2016). Regulation of diversification and affinity maturation of antibodies. International Journal of Molecular Medicine, 38, S43-S43
Open this publication in new window or tab >>Regulation of diversification and affinity maturation of antibodies
Show others...
2016 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 38, p. S43-S43Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Spandidos, 2016
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-126770 (URN)000383733000154 ()
Note

Supplement: 1, Meeting Abstract: 253

Available from: 2016-10-18 Created: 2016-10-13 Last updated: 2022-02-02Bibliographically approved
Grundström, T., Hauser, J., Grundström, C., Kumar, R. & Ahmed, T. (2015). Mechanisms controlling diversification and affinity maturation of antibodies. International Journal of Molecular Medicine, 36, S43-S43
Open this publication in new window or tab >>Mechanisms controlling diversification and affinity maturation of antibodies
Show others...
2015 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 36, p. S43-S43Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-110605 (URN)000361863000157 ()
Note

Supplement: 1 Meeting Abstract: 256

Available from: 2015-10-28 Created: 2015-10-23 Last updated: 2018-06-07Bibliographically approved
Organisations

Search in DiVA

Show all publications