This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tzung, S. P. Articles by Hockenbery, D. M. Search for Related Content PubMed PubMed Citation Articles by Tzung, S. P. Articles by Hockenbery, D. M.

American Journal of Pathology, Vol 150, 1985-1995, Copyright © 1997 by American Society for Investigative Pathology

REGULAR ARTICLES

Expression of Bcl-2 family during liver regeneration and identification of Bcl-x as a delayed early response gene

SP Tzung, N Fausto and DM Hockenbery
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA.

Induction of Bcl-2 and Bcl-x has been demonstrated in mitogen- stimulated lymphocytes in vitro, suggesting that these two apoptosis modulators may also play a role during proliferation. To explore this possibility in a physiological setting, mRNA expression of various Bcl- 2 family members was examined during liver regeneration induced by partial hepatectomy, a well characterized in vivo model of cell cycle progression. After a 60% partial hepatectomy in C3H/HeN mice, the steady-state levels of Bcl-x mRNA exhibited a cyclical pattern, with peaks at 4 hours (early G1) and 48 to 72 hours (G1 phase of the second hepatocyte cell cycle). A1 and Bcl-2 mRNA were not detected, and the levels of two Mcl-1 mRNA species remained low without significant changes. The three pro-apoptotic members of the family, Bak, Bad, and Bax, all showed an early decline in mRNA levels when Bcl-x transcripts increased, followed by later peaks at 12, 24, and 48 to 72 hours, respectively. Experiments were subsequently conducted in C3H/HeJ mice, an endotoxin-resistant strain with slower liver regeneration marked by a protracted G1 phase. Even though immediate-early gene responses measured by c-myc induction remained intact, the timing of Bcl-x mRNA expression was delayed in C3H/HeJ mice. When C3H/HeN mice were pretreated with cycloheximide before hepatectomy, the early peak of Bcl- x mRNA at 4 hours was essentially abrogated whereas the immediate-early gene c-myc was hyperinduced, thus implicating Bcl-x as a delayed early response gene during liver regeneration. Bcl-x was localized in hepatocytes and by both immunohistochemistry and Western blot analysis, Bcl-xL protein reached highest levels at 12 hours (mid-G1), consistent with the expression of a delayed early gene. In summary, the expression profiles of Bcl-2 family members during liver regeneration suggest a cell-cycle-dependent regulation as well as a physiological role for these apoptosis-modulating genes during growth and proliferation.

This article has been cited by other articles:

				B. Hu and L. M. Colletti Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice Am J Physiol Gastrointest Liver Physiol, July 1, 2008; 295(1): G45 - G53. [Abstract] [Full Text] [PDF]

				J. I-J. Leu and D. L. George Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria Genes & Dev., December 1, 2007; 21(23): 3095 - 3109. [Abstract] [Full Text] [PDF]

				I. Katoh, Y. Tomimori, Y. Ikawa, and S.-i. Kurata Dimerization and Processing of Procaspase-9 by Redox Stress in Mitochondria J. Biol. Chem., April 9, 2004; 279(15): 15515 - 15523. [Abstract] [Full Text] [PDF]

				F. Desmots, M. Rissel, D. Gilot, D. Lagadic-Gossmann, F. Morel, C. Guguen-Guillouzo, A. Guillouzo, and P. Loyer Pro-inflammatory Cytokines Tumor Necrosis Factor alpha and Interleukin-6 and Survival Factor Epidermal Growth Factor Positively Regulate the Murine GSTA4 Enzyme in Hepatocytes J. Biol. Chem., May 10, 2002; 277(20): 17892 - 17900. [Abstract] [Full Text] [PDF]

				C. Mitchell, V. O. Mallet, J. E. Guidotti, C. Goulenok, A. Kahn, and H. Gilgenkrantz Liver Repopulation by Bcl-xL Transgenic Hepatocytes Am. J. Pathol., January 1, 2002; 160(1): 31 - 35. [Abstract] [Full Text] [PDF]

				M. L. Adams, R. H. Pierce, M. E. Vail, C. C. White, R. P. Tonge, T. J. Kavanagh, N. Fausto, S. D. Nelson, and S. A. Bruschi Enhanced Acetaminophen Hepatotoxicity in Transgenic Mice Overexpressing BCL-2 Mol. Pharmacol., November 1, 2001; 60(5): 907 - 915. [Abstract] [Full Text] [PDF]

				R. B. Evans-Storms and J. A. Cidlowski Delineation of an Antiapoptotic Action of Glucocorticoids in Hepatoma Cells: The Role of Nuclear Factor-{kappa}B Endocrinology, May 1, 2000; 141(5): 1854 - 1862. [Abstract] [Full Text] [PDF]

				M. Silva, A. Benito, C. Sanz, F. Prosper, D. Ekhterae, G. Nunez, and J. L. Fernandez-Luna Erythropoietin Can Induce the Expression of Bcl-xL through Stat5 in Erythropoietin-dependent Progenitor Cell Lines J. Biol. Chem., August 6, 1999; 274(32): 22165 - 22169. [Abstract] [Full Text] [PDF]

				N. Shinoura, Y. Yoshida, M. Nishimura, Y. Muramatsu, A. Asai, T. Kirino, and H. Hamada Expression Level of Bcl-2 Determines Anti- or Proapoptotic Function Cancer Res., August 1, 1999; 59(16): 4119 - 4128. [Abstract] [Full Text] [PDF]

				M. Koga, Y. Hiromatsu, A. Jimi, S. Toda, N. Koike, and K. Nonaka Immunohistochemical Analysis of Bcl-2, Bax, and Bak Expression in Thyroid Glands from Patients with Subacute Thyroiditis J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 2221 - 2225. [Abstract] [Full Text]