Dataset Information

Loss of p57^KIP2 expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells.

ABSTRACT: A complete hydatidiform mole (CHM) is androgenetic in origin and characterized by enhanced trophoblastic proliferation and the absence of fetal tissue. In 15 to 20% of cases, CHMs are followed by malignant gestational trophoblastic neoplasms including choriocarcinoma. Aberrant genomic imprinting may be responsible for trophoblast hypertrophy in CHMs, but the detailed mechanisms are still elusive, partly due to the lack of suitable animal or in vitro models. We recently developed a culture system of human trophoblast stem (TS) cells. In this study, we apply this system to CHMs for a better understanding of their molecular pathology. CHM-derived TS cells, designated as TS^mole cells, are morphologically similar to biparental TS (TS^bip) cells and express TS-specific markers such as GATA3, KRT7, and TFAP2C. Interestingly, TS^mole cells have a growth advantage over TS^bip cells only after they reach confluence. We found that p57^KIP2, a maternally expressed gene encoding a cyclin-dependent kinase inhibitor, is strongly induced by increased cell density in TS^bip cells, but not in TS^mole cells. Knockout and overexpression studies suggest that loss of p57^KIP2 expression would be the major cause of the reduced sensitivity to contact inhibition in CHMs. Our findings shed light on the molecular mechanism underlying the pathogenesis of CHMs and could have broad implications in tumorigenesis beyond CHMs because silencing of p57 ^KIP2 is frequently observed in a variety of human tumors.

SUBMITTER: Takahashi S

PROVIDER: S-EPMC6936680 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Loss of p57<sup>KIP2</sup> expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells.

Takahashi Sota S Okae Hiroaki H Kobayashi Norio N Kitamura Akane A Kumada Kanako K Yaegashi Nobuo N Arima Takahiro T

Proceedings of the National Academy of Sciences of the United States of America 20191202 52

A complete hydatidiform mole (CHM) is androgenetic in origin and characterized by enhanced trophoblastic proliferation and the absence of fetal tissue. In 15 to 20% of cases, CHMs are followed by malignant gestational trophoblastic neoplasms including choriocarcinoma. Aberrant genomic imprinting may be responsible for trophoblast hypertrophy in CHMs, but the detailed mechanisms are still elusive, partly due to the lack of suitable animal or in vitro models. We recently developed a culture system ...[more]

PMID: 31792181

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Project description:p57 is a member of the Cip/Kip family of cell cycle inhibitors which restrict the eukaryotic cell cycle by binding to and inhibiting cyclin/CDK complexes. They are considered as tumor suppressors and inactivating genomic mutations of p57 are associated with human overgrowth disorders. Increasing evidence suggests that p57 controls additional cellular processes beyond cell cycle control such as apoptosis, cell migration or transcription. Here we report that p57 can stimulate AP-1 promotor activity. While transactivation by c-Jun is strongly activated by p57, it did not enhance c-Fos induced transcription. This indicates that c-Jun is the target of p57 in the canonical AP-1 heterodimeric transcription factor. We could detect endogenous p57/c-Jun containing complexes in cells by co-immunoprecipitation. The strong stimulation of c-Jun activity is not the consequence of activating phosphorylation in the transactivation domain (TAD) of c-Jun, but rather due to negative interference with c-Jun repressors and positive interference with c-Jun activators. In contrast to full-length p57, the amino- and carboxy-terminal domains of p57 are insufficient for a significant activation of c-Jun induced transcription. When expressed in presence of full length p57, the p57 C-terminus abrogated and the N-terminus enhanced c-Jun activation. This indicates that the C-terminus may bind and sequester a putative activator of c-Jun, whereas the N-terminus may sequester a c-Jun repressor. Interestingly, the p57 aminoterminus is sufficient for binding to the two c-Jun repressors HDAC1 and HDAC3. These data are consistent with a model of c-Jun activation where p57 is a part of large nuclear remodeling/transcription complexes. p57 might stimulate transcription by inhibiting transcription repressor proteins like HDACs via its N-terminus and/or attracting transcription activators through its C-terminus. These data suggest that in addition to its role as a CDK inhibitor and tumor suppressor, p57 may also exert tumor promoting functions by activation of the proto-oncoprotein c-Jun.

Dataset Information

Loss of p57^KIP2 expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells.

Publications

Loss of p57<sup>KIP2</sup> expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells.

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Dataset Information

Loss of p57KIP2 expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells.

Publications

Loss of p57<sup>KIP2</sup> expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Loss of p57^KIP2 expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells.