Autoinhibitory regulation of p73 by ΔNp73 to modulate cell survival and death through a p73-specific target element within the ΔNp73 promoter

被引:165
作者
Nakagawa, T
Takahashi, M
Ozaki, T
Watanabe, K
Todo, S
Mizuguchi, H
Hayakawa, T
Nakagawara, A
机构
[1] Childrens Canc Res Inst, Div Biochem, Chuoh Ku, Chiba 2608717, Japan
[2] Hokkaido Univ, Sch Med, Dept Gen Surg, Kita Ku, Sapporo, Hokkaido 0608638, Japan
[3] Natl Inst Hlth Sci, Div Biol Chem & Biol, Setagaya Ku, Tokyo 1588501, Japan
关键词
D O I
10.1128/MCB.22.8.2575-2585.2002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
p73 is a p53-related tumor suppressor but is also induced by oncogene products such as E2F-1, raising a question as to whether p73 is a tumor suppressor gene or oncogene. Unlike p53, p73 has several variants, including DeltaNp73, which lacks the NH2-terminal transactivation domain. Although, in developing neurons, DeltaNp73 is expressed abundantly and seems to inhibit the proapoptotic function of p53, the role of p73 and DeltaNp73 and their regulatory mechanism in cell growth and differentiation are poorly understood. Here we report that p73, but not p53, directly activates the transcription of endogenous Delta-Np73 by binding to the p73-specific target element located at positions -76 to -57 within the DeltaNp73 promoter region. The activation of DeltaNp73 promoter by p63 was marginal. DeltaNp73 was associated with p73alpha, p73beta, and p53, as demonstrated by immunoprecipitation assays, and inhibited their transactivation activities when we used reporters of Mdm2, Bax, or DeltaNp73 itself in SAOS-2 cells. Furthermore, induction or overexpression of DeltaNp73 promoted cell survival by competing with p53 and p73 itself. Thus, our results suggest that the negative feedback regulation of p73 by its target DeltaNp73 is a novel autoregulatory system for modulating cell survival and death.
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页码:2575 / 2585
页数:11
相关论文
共 63 条
  • [1] ZBP-89 promotes growth arrest through stabilization of p53
    Bai, LG
    Merchant, JL
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2001, 21 (14) : 4670 - 4683
  • [2] p14ARF links the tumour suppressors RB and p53
    Bates, S
    Phillips, AC
    Clark, PA
    Stott, F
    Peters, G
    Ludwig, RL
    Vousden, KH
    [J]. NATURE, 1998, 395 (6698) : 124 - 125
  • [3] Chen CL, 2000, CLIN CANCER RES, V6, P3910
  • [4] p73 and p63 are homotetramers capable of weak heterotypic interactions with each other but not with p53
    Davison, TS
    Vagner, C
    Kaghad, M
    Ayed, A
    Caput, D
    Arrowsmith, CH
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (26) : 18709 - 18714
  • [5] Induction of neuronal differentiation by p73 in a neuroblastoma cell line
    De Laurenzi, V
    Raschellá, G
    Barcaroli, D
    Annicchiarico-Petruzzelli, M
    Ranalli, M
    Catani, MV
    Tanno, B
    Costanzo, A
    Levrero, M
    Melino, G
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (20) : 15226 - 15231
  • [6] Additional complexity in p73:: induction by mitogens in lymphoid cells and identification of two new splicing variants ε and ζ
    De Laurenzi, V
    Catani, MV
    Terrinoni, A
    Corazzari, M
    Melino, G
    Costanzo, A
    Levrero, M
    Knight, RA
    [J]. CELL DEATH AND DIFFERENTIATION, 1999, 6 (05) : 389 - 390
  • [7] Two new p73 splice variants, γ and δ, with different transcriptional activity
    De Laurenzi, V
    Costanzo, A
    Barcaroli, D
    Terrinoni, A
    Falco, M
    Annicchiarico-Petruzzeli, M
    Levrero, M
    Melino, G
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1998, 188 (09) : 1763 - 1768
  • [8] Di Como CJ, 1999, MOL CELL BIOL, V19, P1438
  • [9] Inactivation of the p53-homologue p73 by the mdm2-oncoprotein
    Dobbelstein, M
    Wienzek, S
    König, C
    Roth, J
    [J]. ONCOGENE, 1999, 18 (12) : 2101 - 2106
  • [10] Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells
    Elbashir, SM
    Harborth, J
    Lendeckel, W
    Yalcin, A
    Weber, K
    Tuschl, T
    [J]. NATURE, 2001, 411 (6836) : 494 - 498