Insulin inhibition of protein degradation in cells expressing wild-type and mutant insulin receptors

2003 ◽  
Vol 26 (11) ◽  
pp. 1088-1094 ◽  
Author(s):  
F. G. Hamel ◽  
J. Fawcett ◽  
C. I. Andersen ◽  
P. Berhanu ◽  
R. G. Bennett ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Insulin Receptors ◽  
Wild Type ◽  
Insulin Inhibition ◽  
Mutant Insulin ◽  
In Cells

scholarly journals Insulin activates p21Ras and guanine nucleotide releasing factor in cells expressing wild type and mutant insulin receptors.

1993 ◽  
Vol 268 (27) ◽  
pp. 19998-20001
Author(s):  
B Draznin ◽  
L Chang ◽  
J.W. Leitner ◽  
Y Takata ◽  
J.M. Olefsky
Keyword(s):  
Insulin Receptors ◽  
Guanine Nucleotide ◽  
Wild Type ◽  
Mutant Insulin ◽  
In Cells

scholarly journals Signal transduction pathways from insulin receptors to Ras. Analysis by mutant insulin receptors.

1994 ◽  
Vol 269 (6) ◽  
pp. 4634-4640
Author(s):  
K. Yonezawa ◽  
A. Ando ◽  
Y. Kaburagi ◽  
R. Yamamoto-Honda ◽  
T. Kitamura ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Insulin Receptors ◽  
Signal Transduction Pathways ◽  
Mutant Insulin

Overexpression of cysteine dioxygenase reduces intracellular cysteine and glutathione pools in HepG2/C3A cells

2007 ◽  
Vol 293 (1) ◽  
pp. E62-E69 ◽  
Author(s):  
John E. Dominy ◽  
Jesse Hwang ◽  
Martha H. Stipanuk
Keyword(s):  
Steady State ◽  
Experimental Evidence ◽  
Cysteine Dioxygenase ◽  
Wild Type ◽  
Hepatic Expression ◽  
Direct Experimental Evidence ◽  
Homeostatic Response ◽  
Catabolic Enzyme ◽  
In Cells

Cysteine levels are carefully regulated in mammals to balance metabolic needs against the potential for cytotoxicity. It has been postulated that one of the major regulators of intracellular cysteine levels in mammals is cysteine dioxygenase (CDO). Hepatic expression of this catabolic enzyme increases dramatically in response to increased cysteine availability and may therefore be part of a homeostatic response to shunt excess toxic cysteine to more benign metabolites such as sulfate or taurine. Direct experimental evidence, however, is lacking to support the hypothesis that CDO is capable of altering steady-state intracellular cysteine levels. In this study, we expressed either the wild-type (WT) or a catalytically inactivated mutant (H86A) isoform of CDO in HepG2/C3A cells (which do not express endogenous CDO protein) and cultured them in different concentrations of extracellular cysteine. WT CDO, but not H86A CDO, was capable of reducing intracellular cysteine levels in cells incubated in physiologically relevant concentrations of cysteine. WT CDO also decreased the glutathione pool and potentiated the toxicity of CdCl2. These results demonstrate that CDO is capable of altering intracellular cysteine levels as well as glutathione levels.

scholarly journals Involvement of Heat Shock Protein 90 in the Degradation of Mutant Insulin Receptors by the Proteasome

1998 ◽  
Vol 273 (18) ◽  
pp. 11183-11188 ◽  
Author(s):  
Takeshi Imamura ◽  
Tetsuro Haruta ◽  
Yasumitsu Takata ◽  
Isao Usui ◽  
Minoru Iwata ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Insulin Receptors ◽  
Heat Shock Protein 90 ◽  
Mutant Insulin

scholarly journals DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin D1 function in G1.

1994 ◽  
Vol 125 (3) ◽  
pp. 625-638 ◽  
Author(s):  
J Lukas ◽  
H Müller ◽  
J Bartkova ◽  
D Spitkovsky ◽  
A A Kjerulff ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Complex Formation ◽  
Cyclin D1 ◽  
Cell Lines ◽  
T Antigen ◽  
Regulatory Function ◽  
Retinoblastoma Gene ◽  
Checkpoint Control ◽  
Wild Type ◽  
In Cells

The retinoblastoma gene product (pRB) participates in the regulation of the cell division cycle through complex formation with numerous cellular regulatory proteins including the potentially oncogenic cyclin D1. Extending the current view of the emerging functional interplay between pRB and D-type cyclins, we now report that cyclin D1 expression is positively regulated by pRB. Cyclin D1 mRNA and protein is specifically downregulated in cells expressing SV40 large T antigen, adenovirus E1A, and papillomavirus E7/E6 oncogene products and this effect requires intact RB-binding, CR2 domain of E1A. Exceptionally low expression of cyclin D1 is also seen in genetically RB-deficient cell lines, in which ectopically expressed wild-type pRB results in specific induction of this G1 cyclin. At the functional level, antibody-mediated cyclin D1 knockout experiments demonstrate that the cyclin D1 protein, normally required for G1 progression, is dispensable for passage through the cell cycle in cell lines whose pRB is inactivated through complex formation with T antigen, E1A, or E7 oncoproteins as well as in cells which have suffered loss-of-function mutations of the RB gene. The requirement for cyclin D1 function is not regained upon experimental elevation of cyclin D1 expression in cells with mutant RB, while reintroduction of wild-type RB into RB-deficient cells leads to restoration of the cyclin D1 checkpoint. These results strongly suggest that pRB serves as a major target of cyclin D1 whose cell cycle regulatory function becomes dispensable in cells lacking functional RB. Based on available data including this study, we propose a model for an autoregulatory feedback loop mechanism that regulates both the expression of the cyclin D1 gene and the activity of pRB, thereby contributing to a G1 phase checkpoint control in cycling mammalian cells.

scholarly journals UBL domain of Usp14 and other proteins stimulates proteasome activities and protein degradation in cells

2018 ◽  
Vol 115 (50) ◽  
pp. E11642-E11650 ◽  
Author(s):  
Hyoung Tae Kim ◽  
Alfred L. Goldberg
Keyword(s):  
Protein Degradation ◽  
Atp Hydrolysis ◽  
Deubiquitinating Enzyme ◽  
Wild Type ◽  
Peptide Hydrolysis ◽  
Ubiquitin Chain ◽  
Important Regulator ◽  
General Response ◽  
Ubiquitin Conjugate ◽  
Stimulation Of

The best-known function of ubiquitin-like (UBL) domains in proteins is to enable their binding to 26S proteasomes. The proteasome-associated deubiquitinating enzyme Usp14/UBP6 contains an N-terminal UBL domain and is an important regulator of proteasomal activity. Usp14 by itself represses multiple proteasomal activities but, upon binding a ubiquitin chain, Usp14 stimulates these activities and promotes ubiquitin-conjugate degradation. Here, we demonstrate that Usp14’s UBL domain alone mimics this activation of proteasomes by ubiquitin chains. Addition of this UBL domain to purified 26S proteasomes stimulated the same activities inhibited by Usp14: peptide entry and hydrolysis, protein-dependent ATP hydrolysis, deubiquitination by Rpn11, and the degradation of ubiquitinated and nonubiquitinated proteins. Thus, the binding of Usp14’s UBL (apparently to Rpn1’s T2 site) seems to mediate the activation of proteasomes by ubiquitinated substrates. However, the stimulation of these various activities was greater in proteasomes lacking Usp14 than in wild-type particles and thus is a general response that does not involve some displacement of Usp14. Furthermore, the UBL domains from hHR23 and hPLIC1/UBQLN1 also stimulated peptide hydrolysis, and the expression of hHR23A’s UBL domain in HeLa cells stimulated overall protein degradation. Therefore, many UBL-containing proteins that bind to proteasomes may also enhance allosterically its proteolytic activity.

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