CDK1 dependent phosphorylation of hTERT contributes to cancer progression

Mami Yasukawa; Yoshinari Ando; Taro Yamashita; Yoko Matsuda; Shisako Shoji; Masaki S. Morioka; Hideya Kawaji; Kumiko Shiozawa; Takaya Abe; Shinji Yamada; Mika K. Kaneko; Yukinari Kato; Yasuhide Furuta; Tadashi Kondo; Mikako Shirouzu; Yoshihide Hayashizaki; Shuichi Kaneko; Kenkichi Masutomi

doi:10.1101/556514

CDK1 dependent phosphorylation of hTERT contributes to cancer progression

Mami Yasukawa, Yoshinari Ando, Taro Yamashita, Yoko Matsuda, Shisako Shoji, Masaki S. Morioka, Hideya Kawaji, Kumiko Shiozawa, Takaya Abe, Shinji Yamada, Mika K. Kaneko, Yukinari Kato, Yasuhide Furuta, Tadashi Kondo, Mikako Shirouzu, Yoshihide Hayashizaki, Shuichi Kaneko, Kenkichi Masutomi

Research output: Contribution to journal › Article › peer-review

Abstract

The telomerase reverse transcriptase is upregulated in the majority of human cancers and contributes directly to cell transformation. Here we report that hTERT is phosphorylated at threonine 249 during mitosis by the serine/threonine kinase CDK1. Clinicopathological analyses revealed that phosphorylation of hTERT at threonine 249 occurs more frequently in advanced cancers. Using CRISPR/Cas9 genome editing, we introduced substitution mutations at threonine 249 in the endogenous hTERT locus and found that phosphorylation of threonine 249 is necessary for hTERT-mediated RNA dependent RNA polymerase (RdRP) activity but dispensable for reverse transcriptase activity. Cap Analysis of Gene Expression (CAGE) demonstrated that hTERT phosphorylation at 249 regulates the expression of specific genes that are necessary for cancer cell proliferation and tumor formation. These observations indicate that phosphorylation at threonine 249 regulates hTERT RdRP and contributes to cancer progression in a telomerase independent manner.

Original language	English
Journal	Unknown Journal
DOIs	https://doi.org/10.1101/556514
Publication status	Published - 2019 Feb 21

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Immunology and Microbiology(all)
Neuroscience(all)
Pharmacology, Toxicology and Pharmaceutics(all)

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CDK1 dependent phosphorylation of hTERT contributes to cancer progression. / Yasukawa, Mami; Ando, Yoshinari; Yamashita, Taro; Matsuda, Yoko; Shoji, Shisako; Morioka, Masaki S.; Kawaji, Hideya; Shiozawa, Kumiko; Abe, Takaya; Yamada, Shinji; Kaneko, Mika K.; Kato, Yukinari; Furuta, Yasuhide; Kondo, Tadashi; Shirouzu, Mikako; Hayashizaki, Yoshihide; Kaneko, Shuichi; Masutomi, Kenkichi.

In: Unknown Journal, 21.02.2019.

Research output: Contribution to journal › Article › peer-review

Yasukawa, Mami ; Ando, Yoshinari ; Yamashita, Taro ; Matsuda, Yoko ; Shoji, Shisako ; Morioka, Masaki S. ; Kawaji, Hideya ; Shiozawa, Kumiko ; Abe, Takaya ; Yamada, Shinji ; Kaneko, Mika K. ; Kato, Yukinari ; Furuta, Yasuhide ; Kondo, Tadashi ; Shirouzu, Mikako ; Hayashizaki, Yoshihide ; Kaneko, Shuichi ; Masutomi, Kenkichi. / CDK1 dependent phosphorylation of hTERT contributes to cancer progression. In: Unknown Journal. 2019.

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title = "CDK1 dependent phosphorylation of hTERT contributes to cancer progression",

abstract = "The telomerase reverse transcriptase is upregulated in the majority of human cancers and contributes directly to cell transformation. Here we report that hTERT is phosphorylated at threonine 249 during mitosis by the serine/threonine kinase CDK1. Clinicopathological analyses revealed that phosphorylation of hTERT at threonine 249 occurs more frequently in advanced cancers. Using CRISPR/Cas9 genome editing, we introduced substitution mutations at threonine 249 in the endogenous hTERT locus and found that phosphorylation of threonine 249 is necessary for hTERT-mediated RNA dependent RNA polymerase (RdRP) activity but dispensable for reverse transcriptase activity. Cap Analysis of Gene Expression (CAGE) demonstrated that hTERT phosphorylation at 249 regulates the expression of specific genes that are necessary for cancer cell proliferation and tumor formation. These observations indicate that phosphorylation at threonine 249 regulates hTERT RdRP and contributes to cancer progression in a telomerase independent manner.",

author = "Mami Yasukawa and Yoshinari Ando and Taro Yamashita and Yoko Matsuda and Shisako Shoji and Morioka, {Masaki S.} and Hideya Kawaji and Kumiko Shiozawa and Takaya Abe and Shinji Yamada and Kaneko, {Mika K.} and Yukinari Kato and Yasuhide Furuta and Tadashi Kondo and Mikako Shirouzu and Yoshihide Hayashizaki and Shuichi Kaneko and Kenkichi Masutomi",

note = "Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

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T1 - CDK1 dependent phosphorylation of hTERT contributes to cancer progression

AU - Yasukawa, Mami

AU - Ando, Yoshinari

AU - Yamashita, Taro

AU - Matsuda, Yoko

AU - Shoji, Shisako

AU - Morioka, Masaki S.

AU - Kawaji, Hideya

AU - Shiozawa, Kumiko

AU - Abe, Takaya

AU - Yamada, Shinji

AU - Kaneko, Mika K.

AU - Kato, Yukinari

AU - Furuta, Yasuhide

AU - Kondo, Tadashi

AU - Shirouzu, Mikako

AU - Hayashizaki, Yoshihide

AU - Kaneko, Shuichi

AU - Masutomi, Kenkichi

N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2019/2/21

Y1 - 2019/2/21

N2 - The telomerase reverse transcriptase is upregulated in the majority of human cancers and contributes directly to cell transformation. Here we report that hTERT is phosphorylated at threonine 249 during mitosis by the serine/threonine kinase CDK1. Clinicopathological analyses revealed that phosphorylation of hTERT at threonine 249 occurs more frequently in advanced cancers. Using CRISPR/Cas9 genome editing, we introduced substitution mutations at threonine 249 in the endogenous hTERT locus and found that phosphorylation of threonine 249 is necessary for hTERT-mediated RNA dependent RNA polymerase (RdRP) activity but dispensable for reverse transcriptase activity. Cap Analysis of Gene Expression (CAGE) demonstrated that hTERT phosphorylation at 249 regulates the expression of specific genes that are necessary for cancer cell proliferation and tumor formation. These observations indicate that phosphorylation at threonine 249 regulates hTERT RdRP and contributes to cancer progression in a telomerase independent manner.

AB - The telomerase reverse transcriptase is upregulated in the majority of human cancers and contributes directly to cell transformation. Here we report that hTERT is phosphorylated at threonine 249 during mitosis by the serine/threonine kinase CDK1. Clinicopathological analyses revealed that phosphorylation of hTERT at threonine 249 occurs more frequently in advanced cancers. Using CRISPR/Cas9 genome editing, we introduced substitution mutations at threonine 249 in the endogenous hTERT locus and found that phosphorylation of threonine 249 is necessary for hTERT-mediated RNA dependent RNA polymerase (RdRP) activity but dispensable for reverse transcriptase activity. Cap Analysis of Gene Expression (CAGE) demonstrated that hTERT phosphorylation at 249 regulates the expression of specific genes that are necessary for cancer cell proliferation and tumor formation. These observations indicate that phosphorylation at threonine 249 regulates hTERT RdRP and contributes to cancer progression in a telomerase independent manner.

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