A novel human dynactin-associated protein, dynAP, promotes activation of Akt, and ergosterol-related compounds induce dynAP-dependent apoptosis of human cancer cells

Tatsuki Kunoh, Takanori Noda, Koichi Koseki, Masayuki Sekigawa, Motoki Takagi, Kazuo Shin-ya, Naoki Goshima, Shun Ichiro Iemura, Tohru Natsume, Shu Ichi Wada, Yukio Mukai, Shinji Ohta, Ryuzo Sasaki, Tamio Mizukami

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

There are several human genes that may encode proteins whose functions remain unknown. To find clues to their functions, we used the mutant yeast defective in Mad2, a component of the spindle checkpoint complex. Phenotypes that were provoked by the expression of a human C18orf26 protein in the mutant yeast encouraged further characterization of this protein in human cells. This protein was designated dynAP (dynactin-associated protein) because of its interaction with dynactin subunits that comprised a microtubule-based motor protein complex. The dynAP is a transmembrane protein localizing to Golgi apparatus and plasma membrane in a microtubule-dependent manner. This protein was expressed in half of human cancer cell lines but barely in normal human fibroblasts tested. The SV40-transformed fibroblasts expressed dynAP. Importantly, the expression of dynAP activated Akt (also known as protein kinase B) by promoting Ser473 phosphorylation required for the full activation, whereas knockdown of dynAP abolished this activation. The ergosterol-related compounds identified by the yeast cell-based high-throughput screen abrogated activation of Akt and induced apoptosis in a dynAP-dependent manner. We propose a possible advantage of dynAP expression in cancer cells; the survival of cancer cells that express dynAP is supported by dynAP-induced activation of Akt, sustaining high rates of proliferation. The inactivation of dynAP by the selected compounds nullifies this advantage, and thereby, the apoptotic machinery is allowed to operate. Taken together, dynAP can be a new target for cancer therapy, and the selected chemicals are useful for developing a new class of anticancer drugs.

Original languageEnglish
Pages (from-to)2934-2942
Number of pages9
JournalMolecular Cancer Therapeutics
Volume9
Issue number11
DOIs
Publication statusPublished - Nov 2010
Externally publishedYes

Fingerprint

Ergosterol
Apoptosis
Neoplasms
Proteins
Dynactin Complex
Human DynAP protein
Yeasts
Microtubules
Fibroblasts
Proto-Oncogene Proteins c-akt

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A novel human dynactin-associated protein, dynAP, promotes activation of Akt, and ergosterol-related compounds induce dynAP-dependent apoptosis of human cancer cells. / Kunoh, Tatsuki; Noda, Takanori; Koseki, Koichi; Sekigawa, Masayuki; Takagi, Motoki; Shin-ya, Kazuo; Goshima, Naoki; Iemura, Shun Ichiro; Natsume, Tohru; Wada, Shu Ichi; Mukai, Yukio; Ohta, Shinji; Sasaki, Ryuzo; Mizukami, Tamio.

In: Molecular Cancer Therapeutics, Vol. 9, No. 11, 11.2010, p. 2934-2942.

Research output: Contribution to journalArticle

Kunoh, T, Noda, T, Koseki, K, Sekigawa, M, Takagi, M, Shin-ya, K, Goshima, N, Iemura, SI, Natsume, T, Wada, SI, Mukai, Y, Ohta, S, Sasaki, R & Mizukami, T 2010, 'A novel human dynactin-associated protein, dynAP, promotes activation of Akt, and ergosterol-related compounds induce dynAP-dependent apoptosis of human cancer cells', Molecular Cancer Therapeutics, vol. 9, no. 11, pp. 2934-2942. https://doi.org/10.1158/1535-7163.MCT-10-0730
Kunoh, Tatsuki ; Noda, Takanori ; Koseki, Koichi ; Sekigawa, Masayuki ; Takagi, Motoki ; Shin-ya, Kazuo ; Goshima, Naoki ; Iemura, Shun Ichiro ; Natsume, Tohru ; Wada, Shu Ichi ; Mukai, Yukio ; Ohta, Shinji ; Sasaki, Ryuzo ; Mizukami, Tamio. / A novel human dynactin-associated protein, dynAP, promotes activation of Akt, and ergosterol-related compounds induce dynAP-dependent apoptosis of human cancer cells. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 11. pp. 2934-2942.
@article{487670726501477eb65a3f6e0cc89cd0,
title = "A novel human dynactin-associated protein, dynAP, promotes activation of Akt, and ergosterol-related compounds induce dynAP-dependent apoptosis of human cancer cells",
abstract = "There are several human genes that may encode proteins whose functions remain unknown. To find clues to their functions, we used the mutant yeast defective in Mad2, a component of the spindle checkpoint complex. Phenotypes that were provoked by the expression of a human C18orf26 protein in the mutant yeast encouraged further characterization of this protein in human cells. This protein was designated dynAP (dynactin-associated protein) because of its interaction with dynactin subunits that comprised a microtubule-based motor protein complex. The dynAP is a transmembrane protein localizing to Golgi apparatus and plasma membrane in a microtubule-dependent manner. This protein was expressed in half of human cancer cell lines but barely in normal human fibroblasts tested. The SV40-transformed fibroblasts expressed dynAP. Importantly, the expression of dynAP activated Akt (also known as protein kinase B) by promoting Ser473 phosphorylation required for the full activation, whereas knockdown of dynAP abolished this activation. The ergosterol-related compounds identified by the yeast cell-based high-throughput screen abrogated activation of Akt and induced apoptosis in a dynAP-dependent manner. We propose a possible advantage of dynAP expression in cancer cells; the survival of cancer cells that express dynAP is supported by dynAP-induced activation of Akt, sustaining high rates of proliferation. The inactivation of dynAP by the selected compounds nullifies this advantage, and thereby, the apoptotic machinery is allowed to operate. Taken together, dynAP can be a new target for cancer therapy, and the selected chemicals are useful for developing a new class of anticancer drugs.",
author = "Tatsuki Kunoh and Takanori Noda and Koichi Koseki and Masayuki Sekigawa and Motoki Takagi and Kazuo Shin-ya and Naoki Goshima and Iemura, {Shun Ichiro} and Tohru Natsume and Wada, {Shu Ichi} and Yukio Mukai and Shinji Ohta and Ryuzo Sasaki and Tamio Mizukami",
year = "2010",
month = "11",
doi = "10.1158/1535-7163.MCT-10-0730",
language = "English",
volume = "9",
pages = "2934--2942",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

TY - JOUR

T1 - A novel human dynactin-associated protein, dynAP, promotes activation of Akt, and ergosterol-related compounds induce dynAP-dependent apoptosis of human cancer cells

AU - Kunoh, Tatsuki

AU - Noda, Takanori

AU - Koseki, Koichi

AU - Sekigawa, Masayuki

AU - Takagi, Motoki

AU - Shin-ya, Kazuo

AU - Goshima, Naoki

AU - Iemura, Shun Ichiro

AU - Natsume, Tohru

AU - Wada, Shu Ichi

AU - Mukai, Yukio

AU - Ohta, Shinji

AU - Sasaki, Ryuzo

AU - Mizukami, Tamio

PY - 2010/11

Y1 - 2010/11

N2 - There are several human genes that may encode proteins whose functions remain unknown. To find clues to their functions, we used the mutant yeast defective in Mad2, a component of the spindle checkpoint complex. Phenotypes that were provoked by the expression of a human C18orf26 protein in the mutant yeast encouraged further characterization of this protein in human cells. This protein was designated dynAP (dynactin-associated protein) because of its interaction with dynactin subunits that comprised a microtubule-based motor protein complex. The dynAP is a transmembrane protein localizing to Golgi apparatus and plasma membrane in a microtubule-dependent manner. This protein was expressed in half of human cancer cell lines but barely in normal human fibroblasts tested. The SV40-transformed fibroblasts expressed dynAP. Importantly, the expression of dynAP activated Akt (also known as protein kinase B) by promoting Ser473 phosphorylation required for the full activation, whereas knockdown of dynAP abolished this activation. The ergosterol-related compounds identified by the yeast cell-based high-throughput screen abrogated activation of Akt and induced apoptosis in a dynAP-dependent manner. We propose a possible advantage of dynAP expression in cancer cells; the survival of cancer cells that express dynAP is supported by dynAP-induced activation of Akt, sustaining high rates of proliferation. The inactivation of dynAP by the selected compounds nullifies this advantage, and thereby, the apoptotic machinery is allowed to operate. Taken together, dynAP can be a new target for cancer therapy, and the selected chemicals are useful for developing a new class of anticancer drugs.

AB - There are several human genes that may encode proteins whose functions remain unknown. To find clues to their functions, we used the mutant yeast defective in Mad2, a component of the spindle checkpoint complex. Phenotypes that were provoked by the expression of a human C18orf26 protein in the mutant yeast encouraged further characterization of this protein in human cells. This protein was designated dynAP (dynactin-associated protein) because of its interaction with dynactin subunits that comprised a microtubule-based motor protein complex. The dynAP is a transmembrane protein localizing to Golgi apparatus and plasma membrane in a microtubule-dependent manner. This protein was expressed in half of human cancer cell lines but barely in normal human fibroblasts tested. The SV40-transformed fibroblasts expressed dynAP. Importantly, the expression of dynAP activated Akt (also known as protein kinase B) by promoting Ser473 phosphorylation required for the full activation, whereas knockdown of dynAP abolished this activation. The ergosterol-related compounds identified by the yeast cell-based high-throughput screen abrogated activation of Akt and induced apoptosis in a dynAP-dependent manner. We propose a possible advantage of dynAP expression in cancer cells; the survival of cancer cells that express dynAP is supported by dynAP-induced activation of Akt, sustaining high rates of proliferation. The inactivation of dynAP by the selected compounds nullifies this advantage, and thereby, the apoptotic machinery is allowed to operate. Taken together, dynAP can be a new target for cancer therapy, and the selected chemicals are useful for developing a new class of anticancer drugs.

UR - http://www.scopus.com/inward/record.url?scp=78649683101&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78649683101&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-10-0730

DO - 10.1158/1535-7163.MCT-10-0730

M3 - Article

C2 - 20978158

AN - SCOPUS:78649683101

VL - 9

SP - 2934

EP - 2942

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 11

ER -