TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma

Publication Date:
2018-06-22
Publisher:
American Society of Hematology (ASH)
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
Medicine
Keywords:
Lymphoid Neoplasia
Published by:
http://www.hematology.org/
_version_ 1836398981217779712
autor Jethwa, A., Słabicki, M., Hüllein, J., Jentzsch, M., Dalal, V., Rabe, S., Wagner, L., Walther, T., Klapper, W., MMML Network Project, Bohnenberger, H., Rettel, M., Lu, J., Smits, A. H., Stein, F., Savitski, M. M., Huber, W., Aylon, Y., Oren, M., Zenz, T.
beschreibung Tumors accumulate high levels of mutant p53 (mutp53), which contributes to mutp53 gain-of-function properties. The mechanisms that underlie such excessive accumulation are not fully understood. To discover regulators of mutp53 protein accumulation, we performed a large-scale RNA interference screen in a Burkitt lymphoma cell line model. We identified transformation/transcription domain-associated protein (TRRAP), a constituent of several histone acetyltransferase complexes, as a critical positive regulator of both mutp53 and wild-type p53 levels. TRRAP silencing attenuated p53 accumulation in lymphoma and colon cancer models, whereas TRRAP overexpression increased mutp53 levels, suggesting a role for TRRAP across cancer entities and p53 mutations. Through clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 screening, we identified a 109-amino-acid region in the N-terminal HEAT repeat region of TRRAP that was crucial for mutp53 stabilization and cell proliferation. Mass spectrometric analysis of the mutp53 interactome indicated that TRRAP silencing caused degradation of mutp53 via the MDM2-proteasome axis. This suggests that TRRAP is vital for maintaining mutp53 levels by shielding it against the natural p53 degradation machinery. To identify drugs that alleviated p53 accumulation similarly to TRRAP silencing, we performed a small-molecule drug screen and found that inhibition of histone deacetylases (HDACs), specifically HDAC1/2/3, decreased p53 levels to a comparable extent. In summary, here we identify TRRAP as a key regulator of p53 levels and link acetylation-modifying complexes to p53 protein stability. Our findings may provide clues for therapeutic targeting of mutp53 in lymphoma and other cancers.
citation_standardnr 6289598
datenlieferant ipn_articles
feed_id 310
feed_publisher American Society of Hematology (ASH)
feed_publisher_url http://www.hematology.org/
insertion_date 2018-06-22
journaleissn 1528-0020
journalissn 0006-4971
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher American Society of Hematology (ASH)
quelle Blood
relation http://www.bloodjournal.org/cgi/content/short/131/25/2789?rss=1
schlagwort Lymphoid Neoplasia
search_space articles
shingle_author_1 Jethwa, A., Słabicki, M., Hüllein, J., Jentzsch, M., Dalal, V., Rabe, S., Wagner, L., Walther, T., Klapper, W., MMML Network Project, Bohnenberger, H., Rettel, M., Lu, J., Smits, A. H., Stein, F., Savitski, M. M., Huber, W., Aylon, Y., Oren, M., Zenz, T.
shingle_author_2 Jethwa, A., Słabicki, M., Hüllein, J., Jentzsch, M., Dalal, V., Rabe, S., Wagner, L., Walther, T., Klapper, W., MMML Network Project, Bohnenberger, H., Rettel, M., Lu, J., Smits, A. H., Stein, F., Savitski, M. M., Huber, W., Aylon, Y., Oren, M., Zenz, T.
shingle_author_3 Jethwa, A., Słabicki, M., Hüllein, J., Jentzsch, M., Dalal, V., Rabe, S., Wagner, L., Walther, T., Klapper, W., MMML Network Project, Bohnenberger, H., Rettel, M., Lu, J., Smits, A. H., Stein, F., Savitski, M. M., Huber, W., Aylon, Y., Oren, M., Zenz, T.
shingle_author_4 Jethwa, A., Słabicki, M., Hüllein, J., Jentzsch, M., Dalal, V., Rabe, S., Wagner, L., Walther, T., Klapper, W., MMML Network Project, Bohnenberger, H., Rettel, M., Lu, J., Smits, A. H., Stein, F., Savitski, M. M., Huber, W., Aylon, Y., Oren, M., Zenz, T.
shingle_catch_all_1 TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma
Lymphoid Neoplasia
Tumors accumulate high levels of mutant p53 (mutp53), which contributes to mutp53 gain-of-function properties. The mechanisms that underlie such excessive accumulation are not fully understood. To discover regulators of mutp53 protein accumulation, we performed a large-scale RNA interference screen in a Burkitt lymphoma cell line model. We identified transformation/transcription domain-associated protein (TRRAP), a constituent of several histone acetyltransferase complexes, as a critical positive regulator of both mutp53 and wild-type p53 levels. TRRAP silencing attenuated p53 accumulation in lymphoma and colon cancer models, whereas TRRAP overexpression increased mutp53 levels, suggesting a role for TRRAP across cancer entities and p53 mutations. Through clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 screening, we identified a 109-amino-acid region in the N-terminal HEAT repeat region of TRRAP that was crucial for mutp53 stabilization and cell proliferation. Mass spectrometric analysis of the mutp53 interactome indicated that TRRAP silencing caused degradation of mutp53 via the MDM2-proteasome axis. This suggests that TRRAP is vital for maintaining mutp53 levels by shielding it against the natural p53 degradation machinery. To identify drugs that alleviated p53 accumulation similarly to TRRAP silencing, we performed a small-molecule drug screen and found that inhibition of histone deacetylases (HDACs), specifically HDAC1/2/3, decreased p53 levels to a comparable extent. In summary, here we identify TRRAP as a key regulator of p53 levels and link acetylation-modifying complexes to p53 protein stability. Our findings may provide clues for therapeutic targeting of mutp53 in lymphoma and other cancers.
Jethwa, A., Słabicki, M., Hüllein, J., Jentzsch, M., Dalal, V., Rabe, S., Wagner, L., Walther, T., Klapper, W., MMML Network Project, Bohnenberger, H., Rettel, M., Lu, J., Smits, A. H., Stein, F., Savitski, M. M., Huber, W., Aylon, Y., Oren, M., Zenz, T.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_catch_all_2 TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma
Lymphoid Neoplasia
Tumors accumulate high levels of mutant p53 (mutp53), which contributes to mutp53 gain-of-function properties. The mechanisms that underlie such excessive accumulation are not fully understood. To discover regulators of mutp53 protein accumulation, we performed a large-scale RNA interference screen in a Burkitt lymphoma cell line model. We identified transformation/transcription domain-associated protein (TRRAP), a constituent of several histone acetyltransferase complexes, as a critical positive regulator of both mutp53 and wild-type p53 levels. TRRAP silencing attenuated p53 accumulation in lymphoma and colon cancer models, whereas TRRAP overexpression increased mutp53 levels, suggesting a role for TRRAP across cancer entities and p53 mutations. Through clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 screening, we identified a 109-amino-acid region in the N-terminal HEAT repeat region of TRRAP that was crucial for mutp53 stabilization and cell proliferation. Mass spectrometric analysis of the mutp53 interactome indicated that TRRAP silencing caused degradation of mutp53 via the MDM2-proteasome axis. This suggests that TRRAP is vital for maintaining mutp53 levels by shielding it against the natural p53 degradation machinery. To identify drugs that alleviated p53 accumulation similarly to TRRAP silencing, we performed a small-molecule drug screen and found that inhibition of histone deacetylases (HDACs), specifically HDAC1/2/3, decreased p53 levels to a comparable extent. In summary, here we identify TRRAP as a key regulator of p53 levels and link acetylation-modifying complexes to p53 protein stability. Our findings may provide clues for therapeutic targeting of mutp53 in lymphoma and other cancers.
Jethwa, A., Słabicki, M., Hüllein, J., Jentzsch, M., Dalal, V., Rabe, S., Wagner, L., Walther, T., Klapper, W., MMML Network Project, Bohnenberger, H., Rettel, M., Lu, J., Smits, A. H., Stein, F., Savitski, M. M., Huber, W., Aylon, Y., Oren, M., Zenz, T.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_catch_all_3 TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma
Lymphoid Neoplasia
Tumors accumulate high levels of mutant p53 (mutp53), which contributes to mutp53 gain-of-function properties. The mechanisms that underlie such excessive accumulation are not fully understood. To discover regulators of mutp53 protein accumulation, we performed a large-scale RNA interference screen in a Burkitt lymphoma cell line model. We identified transformation/transcription domain-associated protein (TRRAP), a constituent of several histone acetyltransferase complexes, as a critical positive regulator of both mutp53 and wild-type p53 levels. TRRAP silencing attenuated p53 accumulation in lymphoma and colon cancer models, whereas TRRAP overexpression increased mutp53 levels, suggesting a role for TRRAP across cancer entities and p53 mutations. Through clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 screening, we identified a 109-amino-acid region in the N-terminal HEAT repeat region of TRRAP that was crucial for mutp53 stabilization and cell proliferation. Mass spectrometric analysis of the mutp53 interactome indicated that TRRAP silencing caused degradation of mutp53 via the MDM2-proteasome axis. This suggests that TRRAP is vital for maintaining mutp53 levels by shielding it against the natural p53 degradation machinery. To identify drugs that alleviated p53 accumulation similarly to TRRAP silencing, we performed a small-molecule drug screen and found that inhibition of histone deacetylases (HDACs), specifically HDAC1/2/3, decreased p53 levels to a comparable extent. In summary, here we identify TRRAP as a key regulator of p53 levels and link acetylation-modifying complexes to p53 protein stability. Our findings may provide clues for therapeutic targeting of mutp53 in lymphoma and other cancers.
Jethwa, A., Słabicki, M., Hüllein, J., Jentzsch, M., Dalal, V., Rabe, S., Wagner, L., Walther, T., Klapper, W., MMML Network Project, Bohnenberger, H., Rettel, M., Lu, J., Smits, A. H., Stein, F., Savitski, M. M., Huber, W., Aylon, Y., Oren, M., Zenz, T.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_catch_all_4 TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma
Lymphoid Neoplasia
Tumors accumulate high levels of mutant p53 (mutp53), which contributes to mutp53 gain-of-function properties. The mechanisms that underlie such excessive accumulation are not fully understood. To discover regulators of mutp53 protein accumulation, we performed a large-scale RNA interference screen in a Burkitt lymphoma cell line model. We identified transformation/transcription domain-associated protein (TRRAP), a constituent of several histone acetyltransferase complexes, as a critical positive regulator of both mutp53 and wild-type p53 levels. TRRAP silencing attenuated p53 accumulation in lymphoma and colon cancer models, whereas TRRAP overexpression increased mutp53 levels, suggesting a role for TRRAP across cancer entities and p53 mutations. Through clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 screening, we identified a 109-amino-acid region in the N-terminal HEAT repeat region of TRRAP that was crucial for mutp53 stabilization and cell proliferation. Mass spectrometric analysis of the mutp53 interactome indicated that TRRAP silencing caused degradation of mutp53 via the MDM2-proteasome axis. This suggests that TRRAP is vital for maintaining mutp53 levels by shielding it against the natural p53 degradation machinery. To identify drugs that alleviated p53 accumulation similarly to TRRAP silencing, we performed a small-molecule drug screen and found that inhibition of histone deacetylases (HDACs), specifically HDAC1/2/3, decreased p53 levels to a comparable extent. In summary, here we identify TRRAP as a key regulator of p53 levels and link acetylation-modifying complexes to p53 protein stability. Our findings may provide clues for therapeutic targeting of mutp53 in lymphoma and other cancers.
Jethwa, A., Słabicki, M., Hüllein, J., Jentzsch, M., Dalal, V., Rabe, S., Wagner, L., Walther, T., Klapper, W., MMML Network Project, Bohnenberger, H., Rettel, M., Lu, J., Smits, A. H., Stein, F., Savitski, M. M., Huber, W., Aylon, Y., Oren, M., Zenz, T.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_title_1 TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma
shingle_title_2 TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma
shingle_title_3 TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma
shingle_title_4 TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma
timestamp 2025-06-30T23:35:42.902Z
titel TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma
titel_suche TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma
topic W
WW-YZ
uid ipn_articles_6289598