Mutations in the Circadian Gene CLOCK in Colorectal Cancer

Pia Alhopuro (Lead / Corresponding author), Mikael Bjorklund (Lead / Corresponding author), Heli Sammalkorpi, Mikko Turunen, Sari Tuupanen, Mia Bistrom, Iina Niittymaki, Heli J. Lehtonen, Teemu Kivioja, Virpi Launonen, Juha Saharinen, Kari Nousiainen, Sampsa Hautaniemi, Kyosti Nuorva, Jukka-Pekka Mecklin, Heikki Jarvinen, Torben Orntoft, Diego Arango, Rainer Lehtonen, Auli Karhu & 2 others Jussi Taipale, Lauri A. Aaltonen

    Research output: Contribution to journalArticle

    47 Citations (Scopus)

    Abstract

    The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G2-M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis. Mol Cancer Res; 8(7); 952-60. (C) 2010 AACR.

    Original languageEnglish
    Pages (from-to)952-960
    Number of pages9
    JournalMolecular Cancer Research
    Volume8
    Issue number7
    DOIs
    Publication statusPublished - Jul 2010

    Keywords

    • REPAIR-DEFICIENT CANCERS
    • TUMOR-SUPPRESSOR
    • PAS DOMAIN
    • CELL-CYCLE
    • SPECIFICITY
    • MECHANISM
    • PACEMAKER
    • MPER2
    • PLAYS

    Cite this

    Alhopuro, P., Bjorklund, M., Sammalkorpi, H., Turunen, M., Tuupanen, S., Bistrom, M., ... Aaltonen, L. A. (2010). Mutations in the Circadian Gene CLOCK in Colorectal Cancer. Molecular Cancer Research, 8(7), 952-960. https://doi.org/10.1158/1541-7786.MCR-10-0086
    Alhopuro, Pia ; Bjorklund, Mikael ; Sammalkorpi, Heli ; Turunen, Mikko ; Tuupanen, Sari ; Bistrom, Mia ; Niittymaki, Iina ; Lehtonen, Heli J. ; Kivioja, Teemu ; Launonen, Virpi ; Saharinen, Juha ; Nousiainen, Kari ; Hautaniemi, Sampsa ; Nuorva, Kyosti ; Mecklin, Jukka-Pekka ; Jarvinen, Heikki ; Orntoft, Torben ; Arango, Diego ; Lehtonen, Rainer ; Karhu, Auli ; Taipale, Jussi ; Aaltonen, Lauri A. / Mutations in the Circadian Gene CLOCK in Colorectal Cancer. In: Molecular Cancer Research. 2010 ; Vol. 8, No. 7. pp. 952-960.
    @article{648c964bda2343b5ab94ffd8e46abdbd,
    title = "Mutations in the Circadian Gene CLOCK in Colorectal Cancer",
    abstract = "The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53{\%} of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G2-M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis. Mol Cancer Res; 8(7); 952-60. (C) 2010 AACR.",
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    author = "Pia Alhopuro and Mikael Bjorklund and Heli Sammalkorpi and Mikko Turunen and Sari Tuupanen and Mia Bistrom and Iina Niittymaki and Lehtonen, {Heli J.} and Teemu Kivioja and Virpi Launonen and Juha Saharinen and Kari Nousiainen and Sampsa Hautaniemi and Kyosti Nuorva and Jukka-Pekka Mecklin and Heikki Jarvinen and Torben Orntoft and Diego Arango and Rainer Lehtonen and Auli Karhu and Jussi Taipale and Aaltonen, {Lauri A.}",
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    Alhopuro, P, Bjorklund, M, Sammalkorpi, H, Turunen, M, Tuupanen, S, Bistrom, M, Niittymaki, I, Lehtonen, HJ, Kivioja, T, Launonen, V, Saharinen, J, Nousiainen, K, Hautaniemi, S, Nuorva, K, Mecklin, J-P, Jarvinen, H, Orntoft, T, Arango, D, Lehtonen, R, Karhu, A, Taipale, J & Aaltonen, LA 2010, 'Mutations in the Circadian Gene CLOCK in Colorectal Cancer', Molecular Cancer Research, vol. 8, no. 7, pp. 952-960. https://doi.org/10.1158/1541-7786.MCR-10-0086

    Mutations in the Circadian Gene CLOCK in Colorectal Cancer. / Alhopuro, Pia (Lead / Corresponding author); Bjorklund, Mikael (Lead / Corresponding author); Sammalkorpi, Heli; Turunen, Mikko; Tuupanen, Sari; Bistrom, Mia; Niittymaki, Iina; Lehtonen, Heli J.; Kivioja, Teemu; Launonen, Virpi; Saharinen, Juha; Nousiainen, Kari; Hautaniemi, Sampsa; Nuorva, Kyosti; Mecklin, Jukka-Pekka; Jarvinen, Heikki; Orntoft, Torben; Arango, Diego; Lehtonen, Rainer; Karhu, Auli; Taipale, Jussi; Aaltonen, Lauri A. (Lead / Corresponding author).

    In: Molecular Cancer Research, Vol. 8, No. 7, 07.2010, p. 952-960.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Mutations in the Circadian Gene CLOCK in Colorectal Cancer

    AU - Alhopuro, Pia

    AU - Bjorklund, Mikael

    AU - Sammalkorpi, Heli

    AU - Turunen, Mikko

    AU - Tuupanen, Sari

    AU - Bistrom, Mia

    AU - Niittymaki, Iina

    AU - Lehtonen, Heli J.

    AU - Kivioja, Teemu

    AU - Launonen, Virpi

    AU - Saharinen, Juha

    AU - Nousiainen, Kari

    AU - Hautaniemi, Sampsa

    AU - Nuorva, Kyosti

    AU - Mecklin, Jukka-Pekka

    AU - Jarvinen, Heikki

    AU - Orntoft, Torben

    AU - Arango, Diego

    AU - Lehtonen, Rainer

    AU - Karhu, Auli

    AU - Taipale, Jussi

    AU - Aaltonen, Lauri A.

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    N2 - The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G2-M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis. Mol Cancer Res; 8(7); 952-60. (C) 2010 AACR.

    AB - The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G2-M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis. Mol Cancer Res; 8(7); 952-60. (C) 2010 AACR.

    KW - REPAIR-DEFICIENT CANCERS

    KW - TUMOR-SUPPRESSOR

    KW - PAS DOMAIN

    KW - CELL-CYCLE

    KW - SPECIFICITY

    KW - MECHANISM

    KW - PACEMAKER

    KW - MPER2

    KW - PLAYS

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    Alhopuro P, Bjorklund M, Sammalkorpi H, Turunen M, Tuupanen S, Bistrom M et al. Mutations in the Circadian Gene CLOCK in Colorectal Cancer. Molecular Cancer Research. 2010 Jul;8(7):952-960. https://doi.org/10.1158/1541-7786.MCR-10-0086