JMJD5

Official Full Name

jumonji domain containing 5

Background

This gene likely encodes a histone lysine demethylase. Studies of a similar protein in mouse indicate a potential role for this protein as a tumor suppressor. Alternatively spliced transcript variants have been described.

Synonyms

jumonji domain containing 5; lysine-specific demethylase 8; FLJ13798; EC 1.14.11.27; JmjC domain-containing protein 5; KDM8; Jumonji domain-containing protein 5; OTTHUMP00000162455;

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Detailed Information

Recent Research

JMJD5 is a Jumonji C domain-containing demethylase/hydroxylase, which is essential in embryological development, osteoclastic maturation, circadian rhythm regulation and cancer metabolism. Furthermore, JMJD5 is a novel binding partner of p53 and it functions as a positive modulator of cell cycle and cell proliferation mainly through the repression of p53 pathway. JMJD5 belongs to an evolutionarily conserved protein family that contains jumonji C (JmjC) domain. Members of this family have been characterized as demethylases or hydroxylases and show crucial functions in various biological processes by targeting histone and nonhistone proteins. JMJD5 is important for cancer growth. JMJD5 was reported to be involved in lysine demethylation and hydroxylation functions. JMJD5 forms complex with the tumor suppressor p53 by interacting with p53 DNA-binding domain (DBD), and negatively regulates its activity.

Down-regulation of JMJD5 resulted in increased expression of multiple p53 downstream genes, such as DNA repair effector P53R2 and the cell cycle inhibitor CDKN1A, only in p53-proficient lung cancer cells. CDKN1A and ectopic expression of JMJD5 not only increased but also rescued CDKN1A transcription. JMJD5 is up-regulated by hypoxia and is crucial for hypoxiainduced cell proliferation. The JMJD5-PKM2 interaction resides at the intersubunit interface region of PKM2, which hinders PKM2 tetramerization and blocks pyruvate kinase activity.

Depletion of JMJD5 inhibited cell proliferation and enhanced adriamycin-induced cell growth suppression in the presence of p53. Some reports show that JMJD5 negatively regulate the expression of p21, a potent cyclin-dependent kinase inhibitor. In mouse embryonic cells, the deficiency of JMJD5 caused upregulation of p21, contributing to cell growth retardation, pluripotency loss of embryonic stem cells, and embryonic lethality. Some reports show that JMJD5 knockdown promoted HCC cell proliferation and in vivo tumorigenicity by accelerating the G1/S transition of the cell cycle; in contrast, ectopic JMJD5 expression had the opposite effects.

JMJD5 negatively regulates the transcriptional activity of p53 through the association with p53 DBD domain, thus interfering p53 pathway dependent cell growth and cell cycle response after DNA damage. JMJD5 was shown to positively regulate cyclin A1 but negatively regulate p53 and p21. JMJD5 depletion could significantly inhibit human CC cell proliferation, migration, and invasion, implying that JMJD5 might be a potential oncogene. Upon DNA damage, the JMJD5–p53 association decreased, and thereby, promoted p53 recruitment to the target genes and stimulated its transcriptional activity. Furthermore, JMJD5 facilitated the cell cycle progression in a p53-dependent manner under both normal and DNA damage conditions.

JMJD5 is necessary for embryonic development, and has a pivotal role in circadian rhythm maintenance, osteoclastogenesis, cancer cell metabolism and proliferation. JMJD5 plays an important role in cell cycle regulation. JMJD5 inhibits HCC cell proliferation mainly by activating CDKN1A expression. JMJD5 is a tumor suppressor gene in HCC pathogenesis, and the epigenetic silencing of JMJD5 promotes HCC cell proliferation by directly downregulating CDKN1A transcription. JMJD5 interacts directly with pyruvate kinase muscle isozyme (PKM) 2 to modulate metabolic flux in cancer cells. JMJD5 knockdown inhibits the transcription of the PKM2–HIF-1α target genes involved in glucose metabolism, resulting in a reduction of glucose uptake and lactate secretion in cancer cells. JMJD5 accelerates the translocation of PKM2 into the nucleus and enhances the binding of HIF-1α to the target genes, paving the way to cancer-specific metabolism in response to low-oxygen challenge.

References:

Huang X, et al. JMJD5 interacts with p53 and negatively regulates p53 function in control of cell cycle and proliferation. BiochimBiophysActa, 2015, 1853(10):2286-2295.
Wu B H, et al. Epigenetic silencing of JMJD5 promotes the proliferation of hepatocellular carcinoma cells by down-regulating the transcription of CDKN1A. Oncotarget, 2016, 7(6):6847-6863.
HungJung Wang, et al. JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α–mediated glucose metabolism. Proceedings of the National Academy of Sciences of the United States of America,2014, 111(1):279-84.
Ru Z, et al. JMJD5 is a potential oncogene for colon carcinogenesis. International Journal of Clinical & Experimental Pathology, 2015, 8(6):6482.

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