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  1. Article ; Online: The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network.

    Boominathan, Lakshmanane

    Cancer metastasis reviews

    2010  Volume 29, Issue 4, Page(s) 613–639

    Abstract: The tumor suppressor p53 homologues, TA-p73, and p63 have been shown to function as tumor suppressors. However, how they function as tumor suppressors remains elusive. Here, I propose a number of tumor suppressor pathways that illustrate how the TA-p73 ... ...

    Abstract The tumor suppressor p53 homologues, TA-p73, and p63 have been shown to function as tumor suppressors. However, how they function as tumor suppressors remains elusive. Here, I propose a number of tumor suppressor pathways that illustrate how the TA-p73 and p63 could function as negative regulators of invasion, metastasis, and cancer stem cells (CSCs) proliferation. Furthermore, I provide molecular insights into how TA-p73 and p63 could function as tumor suppressors. Remarkably, the guardians--p53, p73, and p63--of the genome are in control of most of the known tumor suppressor miRNAs, tumor suppressor genes, and metastasis suppressors by suppressing c-myc through miR-145/let-7/miR-34/TRIM32/PTEN/FBXW7. In particular, p53 and TA-p73/p63 appear to upregulate the expression of (1) tumor suppressor miRNAs, such as let-7, miR-34, miR-15/16a, miR-145, miR-29, miR-26, miR-30, and miR-146a; (2) tumor suppressor genes, such as PTEN, RBs, CDKN1a/b/c, and CDKN2a/b/c/d; (3) metastasis suppressors, such as Raf kinase inhibitory protein, CycG2, and DEC2, and thereby they enlarge their tumor suppressor network to inhibit tumorigenesis, invasion, angiogenesis, migration, metastasis, and CSCs proliferation.
    MeSH term(s) Animals ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Humans ; Mice ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; RNA Processing, Post-Transcriptional ; Trans-Activators/genetics ; Trans-Activators/metabolism ; Transcription Factors ; Tumor Protein p73 ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism
    Chemical Substances DNA-Binding Proteins ; MicroRNAs ; Nuclear Proteins ; Phosphoproteins ; TP63 protein, human ; TP73 protein, human ; Trans-Activators ; Transcription Factors ; Trp63 protein, mouse ; Trp73 protein, mouse ; Tumor Protein p73 ; Tumor Suppressor Protein p53 ; Tumor Suppressor Proteins
    Language English
    Publishing date 2010-09-17
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 604857-2
    ISSN 1573-7233 ; 0167-7659
    ISSN (online) 1573-7233
    ISSN 0167-7659
    DOI 10.1007/s10555-010-9257-9
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  2. Article ; Online: The tumor suppressors p53, p63, and p73 are regulators of microRNA processing complex.

    Boominathan, Lakshmanane

    PloS one

    2010  Volume 5, Issue 5, Page(s) e10615

    Abstract: The tumor suppressors p53, p73, and p63 are known to function as transcription factors. They promote either growth arrest or apoptosis, depending upon the DNA damage. A number of microRNAs (miRNAs) have been shown to function as transcriptional targets ... ...

    Abstract The tumor suppressors p53, p73, and p63 are known to function as transcription factors. They promote either growth arrest or apoptosis, depending upon the DNA damage. A number of microRNAs (miRNAs) have been shown to function as transcriptional targets of p53 and they appear to aid p53 in promoting growth arrest and apoptosis. However, the question of p53/p63/p73 regulating the miRNA processing complex has not been addressed in depth so far. Comparative/computational genomic analysis was performed using Target scan, Mami, and Diana software to identify miRNAs that regulate the miRNA processing complex. Here, I present evidence for the first time that the tumor suppressors p53, p63, and p73 function as both positive and negative regulators of the miRNA processing components. Curated p53-dependent miRNA expression data was used to identify p53-miRs that target the components of the miRNA-processing complex. This analysis suggests that most of the components (mRNAs' 3'UTR) of the miRNA processing complex are targeted by p53-miRs. Remarkably, this data revealed the conserved nature of p53-miRs in targeting a number of components of the miRNA processing complex. p53/p73/p63 appears to regulate the major components of the miRNA processing, such as Drosha-DGCR8, Dicer-TRBP2, and Argonaute proteins. In particular, p53/p73/p63 appears to regulate the processing of miRNAs, such as let-7, miR-200c, miR-143, miR-107, miR-16, miR-145, miR-134, miR-449a, miR-503, and miR-21. Interestingly, there seems to be a phenotypic similarity between p63(-/-) and dicer(-/-) mice, suggesting that p63 and dicer could regulate each other. In addition, p63, p73, and the DGCR8 proteins contain a conserved interaction domain. Further, promoters of a number of components of the miRNA processing machinery, including dicer and P2P-R, contain p53-REs, suggesting that they could be direct transcriptional targets of p63/p73/p53. Together, this study provides mechanistic insights into how p53, p63, and p73 regulate the components of the miRNA processing; and how p53, TA-p63, and TA-p73 regulated miRNAs inhibit tumorigenesis, EMT, metastasis, and cancer stem cell proliferation.
    MeSH term(s) Animals ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation ; Mice ; MicroRNAs/metabolism ; Models, Biological ; Nuclear Proteins/metabolism ; Phosphoproteins/metabolism ; RNA Processing, Post-Transcriptional/genetics ; Response Elements/genetics ; Trans-Activators/metabolism ; Tumor Protein p73 ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/metabolism
    Chemical Substances DNA-Binding Proteins ; MicroRNAs ; Nuclear Proteins ; Phosphoproteins ; Trans-Activators ; Trp63 protein, mouse ; Trp73 protein, mouse ; Tumor Protein p73 ; Tumor Suppressor Protein p53 ; Tumor Suppressor Proteins
    Language English
    Publishing date 2010-05-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0010615
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The tumor suppressors p53, p63, and p73 are regulators of microRNA processing complex.

    Lakshmanane Boominathan

    PLoS ONE, Vol 5, Iss 5, p e

    2010  Volume 10615

    Abstract: The tumor suppressors p53, p73, and p63 are known to function as transcription factors. They promote either growth arrest or apoptosis, depending upon the DNA damage. A number of microRNAs (miRNAs) have been shown to function as transcriptional targets ... ...

    Abstract The tumor suppressors p53, p73, and p63 are known to function as transcription factors. They promote either growth arrest or apoptosis, depending upon the DNA damage. A number of microRNAs (miRNAs) have been shown to function as transcriptional targets of p53 and they appear to aid p53 in promoting growth arrest and apoptosis. However, the question of p53/p63/p73 regulating the miRNA processing complex has not been addressed in depth so far. Comparative/computational genomic analysis was performed using Target scan, Mami, and Diana software to identify miRNAs that regulate the miRNA processing complex. Here, I present evidence for the first time that the tumor suppressors p53, p63, and p73 function as both positive and negative regulators of the miRNA processing components. Curated p53-dependent miRNA expression data was used to identify p53-miRs that target the components of the miRNA-processing complex. This analysis suggests that most of the components (mRNAs' 3'UTR) of the miRNA processing complex are targeted by p53-miRs. Remarkably, this data revealed the conserved nature of p53-miRs in targeting a number of components of the miRNA processing complex. p53/p73/p63 appears to regulate the major components of the miRNA processing, such as Drosha-DGCR8, Dicer-TRBP2, and Argonaute proteins. In particular, p53/p73/p63 appears to regulate the processing of miRNAs, such as let-7, miR-200c, miR-143, miR-107, miR-16, miR-145, miR-134, miR-449a, miR-503, and miR-21. Interestingly, there seems to be a phenotypic similarity between p63(-/-) and dicer(-/-) mice, suggesting that p63 and dicer could regulate each other. In addition, p63, p73, and the DGCR8 proteins contain a conserved interaction domain. Further, promoters of a number of components of the miRNA processing machinery, including dicer and P2P-R, contain p53-REs, suggesting that they could be direct transcriptional targets of p63/p73/p53. Together, this study provides mechanistic insights into how p53, p63, and p73 regulate the components of the miRNA processing; and how p53, TA-p63, and TA-p73 regulated miRNAs inhibit tumorigenesis, EMT, metastasis, and cancer stem cell proliferation.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2010-05-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Some facts and thoughts: p73 as a tumor suppressor gene in the network of tumor suppressors.

    Boominathan, Lakshmanane

    Molecular cancer

    2007  Volume 6, Page(s) 27

    Abstract: The question of whether p73 is a tumor suppressor gene, is not yet answered with full confidence. The lack of spontaneous tumor formation in p73 null mice and infrequent p73 mutations seen in a variety of cancers analyzed would straightaway negate its ... ...

    Abstract The question of whether p73 is a tumor suppressor gene, is not yet answered with full confidence. The lack of spontaneous tumor formation in p73 null mice and infrequent p73 mutations seen in a variety of cancers analyzed would straightaway negate its role as a primary tumor suppressor gene. However, accumulating evidence suggest that p73 gene and its target genes are hypermethylated in the cancer of lymphoid origin. Here I discuss some facts and thoughts that support the idea that p73 could still be a tumor suppressor gene. The tumor suppressor network in which p73 appears to be a participant involves E2F1, JunB, INK4a/p16, ARF/p19, p57kip2 and BRCA1. Knock out of each gene in E2F-1-p73-JunB-p16INK4a network of tumor suppressor proteins result in lymphoma/leukemia formation. Further, I tried to explain why lymphomas are not seen in p73 null mice and why p73 gene is not prone to frequent mutation.
    MeSH term(s) Animals ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/physiology ; Gene Regulatory Networks ; Genes, Tumor Suppressor/physiology ; Humans ; Lymphoma/genetics ; Mice ; Mice, Knockout ; Models, Biological ; Mutation ; Nuclear Proteins/genetics ; Nuclear Proteins/physiology ; Tumor Protein p73 ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/physiology
    Chemical Substances DNA-Binding Proteins ; Nuclear Proteins ; TP73 protein, human ; Trp73 protein, mouse ; Tumor Protein p73 ; Tumor Suppressor Proteins
    Language English
    Publishing date 2007-04-03
    Publishing country England
    Document type Journal Article
    ISSN 1476-4598
    ISSN (online) 1476-4598
    DOI 10.1186/1476-4598-6-27
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  5. Article ; Online: Some facts and thoughts

    Boominathan Lakshmanane

    Molecular Cancer, Vol 6, Iss 1, p

    p73 as a tumor suppressor gene in the network of tumor suppressors

    2007  Volume 27

    Abstract: Abstract The question of whether p73 is a tumor suppressor gene, is not yet answered with full confidence. The lack of spontaneous tumor formation in p73 null mice and infrequent p73 mutations seen in a variety of cancers analyzed would straightaway ... ...

    Abstract Abstract The question of whether p73 is a tumor suppressor gene, is not yet answered with full confidence. The lack of spontaneous tumor formation in p73 null mice and infrequent p73 mutations seen in a variety of cancers analyzed would straightaway negate its role as a primary tumor suppressor gene. However, accumulating evidence suggest that p73 gene and its target genes are hypermethylated in the cancer of lymphoid origin. Here I discuss some facts and thoughts that support the idea that p73 could still be a tumor suppressor gene. The tumor suppressor network in which p73 appears to be a participant involves E2F1, JunB, INK4a/p16, ARF/p19, p57kip2 and BRCA1. Knock out of each gene in E2F-1-p73-JunB-p16INK4a network of tumor suppressor proteins result in lymphoma/leukemia formation. Further, I tried to explain why lymphomas are not seen in p73 null mice and why p73 gene is not prone to frequent mutation.
    Keywords Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
    Subject code 572
    Language English
    Publishing date 2007-04-01T00:00:00Z
    Publisher BioMed Central
    Document type Article ; Online
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  6. Article: c-Jun regulates the stability and activity of the p53 homologue, p73.

    Toh, Wen Hong / Siddique, M M / Boominathan, Lakshmanane / Lin, Kai Wei / Sabapathy, Kanaga

    The Journal of biological chemistry

    2004  Volume 279, Issue 43, Page(s) 44713–44722

    Abstract: Chemotherapeutic drugs and stress signals activate p73, the structural and functional homologue of p53, both by transcriptional activation and post-translational modifications. However, cisplatin, a DNA damage-inducing chemotherapeutic agent, is thought ... ...

    Abstract Chemotherapeutic drugs and stress signals activate p73, the structural and functional homologue of p53, both by transcriptional activation and post-translational modifications. However, cisplatin, a DNA damage-inducing chemotherapeutic agent, is thought to regulate p73 only by affecting its stability through mechanisms involving the MLH-1/c-Abl signaling cascade. Here we show that c-Jun, a component of the AP-1 family of transcription factors, contributes to p73 induction by cisplatin. c-jun(-/-) cells are defective in p73 induction, and ectopic c-Jun expression augments p73 levels. c-Jun-mediated accumulation of p73 requires the transactivation activity of c-Jun and occurs in a c-Abl- and Mdm2-independent manner. c-Jun expression increases p73 half-life by preventing it from proteasome-mediated degradation, resulting in the potentiation of p73-mediated transcriptional activity. Moreover, mouse fibroblasts lacking c-Jun are resistant to cisplatin-induced apoptosis, and reintroduction of c-Jun restores p73 activation and sensitivity to cisplatin. Furthermore, p73-mediated apoptosis is abrogated in c-jun(-/-) cells. Together, these findings demonstrate a possible role for c-Jun in regulating p73 function and highlight the importance of the cooperativity between transcription factors in potentiating apoptosis.
    MeSH term(s) Animals ; Apoptosis ; Blotting, Western ; COS Cells ; Cell Line, Tumor ; Cells, Cultured ; Cisplatin/pharmacology ; DNA/metabolism ; DNA-Binding Proteins/physiology ; Dose-Response Relationship, Drug ; Fibroblasts/metabolism ; Genes, Tumor Suppressor ; Genetic Vectors ; Humans ; Immunoblotting ; Immunoprecipitation ; JNK Mitogen-Activated Protein Kinases/physiology ; Luciferases/metabolism ; Mice ; Nuclear Proteins/metabolism ; Nuclear Proteins/physiology ; Plasmids/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-abl/metabolism ; Proto-Oncogene Proteins c-mdm2 ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Time Factors ; Transcription, Genetic ; Transcriptional Activation ; Transfection ; Transgenes ; Tumor Protein p73 ; Tumor Suppressor Proteins
    Chemical Substances DNA-Binding Proteins ; Nuclear Proteins ; Proto-Oncogene Proteins ; TP73 protein, human ; Trp73 protein, mouse ; Tumor Protein p73 ; Tumor Suppressor Proteins ; DNA (9007-49-2) ; Luciferases (EC 1.13.12.-) ; MDM2 protein, human (EC 2.3.2.27) ; Mdm2 protein, mouse (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; Proto-Oncogene Proteins c-abl (EC 2.7.10.2) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Cisplatin (Q20Q21Q62J)
    Language English
    Publishing date 2004-08-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M407672200
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    Uc I Zs.108: Show issues Location:
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  7. Article: p73 supports cellular growth through c-Jun-dependent AP-1 transactivation.

    Vikhanskaya, Faina / Toh, Wen Hong / Dulloo, Iqbal / Wu, Qiang / Boominathan, Lakshmanane / Ng, Huck Hui / Vousden, Karen H / Sabapathy, Kanaga

    Nature cell biology

    2007  Volume 9, Issue 6, Page(s) 698–705

    Abstract: The cause or consequence of overexpression of p73 (refs 1, 2), the structural and functional homologue of the tumour-suppressor gene product p53 (refs 3, 4), in human cancers is poorly understood. Here, we report a role for p73 in supporting cellular ... ...

    Abstract The cause or consequence of overexpression of p73 (refs 1, 2), the structural and functional homologue of the tumour-suppressor gene product p53 (refs 3, 4), in human cancers is poorly understood. Here, we report a role for p73 in supporting cellular growth through the upregulation of AP-1 transcriptional activity. p73 suppresses growth when overexpressed alone, but synergises with the proto-oncogene c-Jun to promote cellular survival. Conversely, silencing of p73 expression compromises cellular proliferation. Molecular analysis revealed that expression of the AP-1 target-gene product cyclinD1 (ref. 5) is reduced concomitant with p73, but not p53, silencing. Moreover, cyclinD1 was induced by p73 expression in a c-Jun-dependent manner, and was required for p73-mediated cell survival. Furthermore, c-Jun-dependent AP-1 transcriptional activity was augmented by p73 and, consistently, induction of endogenous AP-1 target genes was compromised in the absence of p73. Chromatin immunoprecipitation and electrophoretic mobility shift analysis indicated that p73 enhanced the binding of phosphorylated c-Jun and Fra-1, another AP-1 family member, to AP-1 consensus DNA sequences, by regulating c-Jun phosphorylation and Fra-1 expression. Collectively, our data demonstrates a novel and unexpected role of p73 in augmenting AP-1 transcriptional activity through which it supports cellular growth.
    MeSH term(s) Animals ; COS Cells ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival/genetics ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cells, Cultured ; Chlorocebus aethiops ; Cyclin D1/genetics ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation, Neoplastic/genetics ; Humans ; Mice ; Mice, Knockout ; NIH 3T3 Cells ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Phosphorylation ; Protein Binding/genetics ; Proto-Oncogene Proteins c-fos/genetics ; Proto-Oncogene Proteins c-fos/metabolism ; Proto-Oncogene Proteins c-jun/genetics ; Proto-Oncogene Proteins c-jun/metabolism ; Transcription Factor AP-1/genetics ; Transcription Factor AP-1/metabolism ; Transcriptional Activation/genetics ; Tumor Protein p73 ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; Up-Regulation/genetics
    Chemical Substances DNA-Binding Proteins ; Nuclear Proteins ; Proto-Oncogene Proteins c-fos ; Proto-Oncogene Proteins c-jun ; TP73 protein, human ; Transcription Factor AP-1 ; Trp73 protein, mouse ; Tumor Protein p73 ; Tumor Suppressor Proteins ; fos-related antigen 1 ; Cyclin D1 (136601-57-5)
    Language English
    Publishing date 2007-05-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1474722-4
    ISSN 1476-4679 ; 1465-7392
    ISSN (online) 1476-4679
    ISSN 1465-7392
    DOI 10.1038/ncb1598
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