Prolactin signaling to pim-1 expression: a role for phosphatidylinositol 3-kinase

Krumenacker, Joshua S.; Narang, Vishal S.; Buckley, Donna J.; Buckley, Arthur R.

doi:10.1016/s0165-5728(00)00430-6

Cited by 24 publications

(11 citation statements)

References 56 publications

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“…This hypothesis is supported by the findings that phosphatidylinositol-3 kinase (PI-3k) and nuclear factor-B (NF-B) can contribute to the activation of pim-1 and overexpression of A1, respectively. 38,59 We speculate that enhanced A1 expression and pim-1-induced up-regulation of Bcl-2 expression could exert synergistic/additive antiapoptotic effects, as described before. 29 A1 and Bcl-2 exert their function by heterodimerizing with the proapoptotic proteins to stabilize mitochondrial membranes and prevent the release of cytochrome c. 41,42 Therefore, their functions may be simply additive.…”

Section: Discussionsupporting

confidence: 54%

Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis

Nieborowska-Skorska

Hoser

Kossev

et al. 2002

Blood

108

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Section: Discussionsupporting

confidence: 54%

Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis

Nieborowska-Skorska

Hoser

Kossev

et al. 2002

Blood

108

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“…This observation suggests that a mechanism distinct from the Jak2/Stat pathway is likely coupled to PRL-stimulated bcl-x L expression. We recently demonstrated that PRL-induced pim-1 expression appeared to require activation of PI3K and its downstream intermediate, Akt (Krumenacker et al 2001). Since IL-3 signaling through PI3K and Akt have been reported to regulate expression of bcl-x L in Baf-3 cells (Leverrier et al 1999), it was tempting to speculate that a similar mechanism may be responsible for regulation of its expression by PRL.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of p59 fyn , mitogen-activated protein kinase (MAPK), c-Jun N-terminal Kinase (JNK), and phosphatidylinositol 3-kinase (PI3K) have also been implicated in the survival actions of PRL, in addition to Jak2 (Clevenger & Medaglia 1994, Buckley et al 1994, Al-Sakkaf et al 1996, Schwertfeger et al 2000, Krumenacker et al 2001. Stationary Nb2-11 cells were treated with pharmacological inhibitors of PI3K (LY294002, 10 µM), JNK (SP600125, 25 µM), p38 MAPK (SB203580, 15 µM), or Src (PP1, 10 µM) for 1 h prior to the addition of PRL.…”

Section: Prl Signaling To Bcl-x L Expressionmentioning

confidence: 99%

Prolactin regulation of Bcl-2 family members: increased expression of bcl-xL but not mcl-1 or bad in Nb2-T cells

Kochendoerfer¹,

Krishnan²,

Buckley³

et al. 2003

Journal of Endocrinology

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Prolactin (PRL)-dependent rat pre-T Nb2 (Nb2-11) cell lines serve as a useful model for investigation of mechanisms underlying lactogen-mediated suppression of apoptosis. Glucocorticoids, such as dexamethasone (DEX), induce apoptosis in Nb2-11 cells; the addition of PRL abrogates the cytolytic actions of DEX in this model, presumably because of increased expression of survival genes. In the present study, we investigated whether inhibition of DEX-induced apoptosis by PRL in Nb2-T cells was accompanied by altered expression of Bcl-2 family members, mcl-1, bad or bcl-x L determined by Northern and immunoblot analysis. The results indicated that a 0·9 kb bcl-x L transcript was rapidly induced by PRL. It reached maximal levels within 2 to 4 h (.20-fold) before declining toward basal values. Similar results were obtained in primary cultures of mouse thymocytes exposed to DEX in combination with PRL. In addition to increasing its mRNA expression, PRL also increased Bcl-xL protein levels by 6 h. Moreover, the effect of PRL to increase bcl-x L appeared to reflect direct and indirect mechanisms, since it was attenuated by the inhibition of protein synthesis. Results from other experiments suggest that PRL signaling to bcl-x L expression was independent of the Jak2/Stat pathway but appeared to require activation of a Src tyrosine kinase. In contrast, while a 1·1 kb mcl-1 transcript was detected in proliferating and quiescent cells, PRL did not alter its expression at either mRNA or protein levels. Moreover, neither bad mRNA nor its protein product were detectable under any of the experimental conditions evaluated. We have concluded that bad and mcl-1 are unlikely candidates for apoptosis regulatory genes modulated by PRL. However, the kinetic pattern of PRL-provoked bcl-x L expression is consistent with its playing a role as an apoptosis suppressor in Nb2-T cells and primary cultures of mouse thymocytes exposed to glucocorticoids.

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“…In addition, PIM-1 itself can negatively regulate the JAK/STAT pathway by binding to SOCS proteins, a group of negative regulators of STAT activity (21). PI3K and its downstream effector AKT are also involved in regulation of Pim-1 expression (22,23). Hsp90 is coordinately regulated with PIM-1 and is responsible for the stabilization and function of PIM-1 (24,25).…”

Section: Introductionmentioning

confidence: 99%

PIM-1–specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis

Hu¹,

Li²,

Vandervalk³

et al. 2009

J. Clin. Invest.

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Provirus integration site for Moloney murine leukemia virus (PIM1) is a proto-oncogene that encodes a serine/ threonine kinase with multiple cellular functions. Overexpression of PIM-1 plays a critical role in progression of prostatic and hematopoietic malignancies. Here we describe the generation of a mAb specific for GST-PIM-1, which reacted strongly with most human and mouse cancer tissues and cell lines of prostate, breast, and colon origin but only weakly (if at all) with normal tissues. The mAb binds to PIM-1 in the cytosol and nucleus as well as to PIM-1 on the surface of human and murine cancer cells. Treatment of human and mouse prostate cancer cell lines with the PIM-1-specific mAb resulted in disruption of PIM-1/Hsp90 complexes, decreased PIM-1 and Hsp90 levels, reduced Akt phosphorylation at Ser473, reduced phosphorylation of Bad at Ser112 and Ser136, and increased cleavage of caspase-9, an indicator of activation of the mitochondrial cell death pathway. The mAb induced cancer cell apoptosis and synergistically enhanced antitumor activity when used in combination with cisplatin and epirubicin. In tumor models, the PIM-1-specific mAb substantially inhibited growth of the human prostate cancer cell line DU145 in SCID mice and the mouse prostate cancer cell TRAMP-C1 in C57BL/6 mice. These findings are important because they provide what we believe to be the first in vivo evidence that treatment of prostate cancer may be possible by targeting PIM-1 using an Ab-based therapy.

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Prolactin signaling to pim-1 expression: a role for phosphatidylinositol 3-kinase

Cited by 24 publications

References 56 publications

Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis

Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis

Prolactin regulation of Bcl-2 family members: increased expression of bcl-xL but not mcl-1 or bad in Nb2-T cells

PIM-1–specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis

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