Expression of Bcl-2 Family Member Bid in Normal and Malignant Tissues

Abstract

Bid is the only known Bcl-2 family member that can function as an agonist of proapoptotic Bcl-2-related proteins such as Bax and Bak. Expression of the proapoptotic Bcl-2 family protein Bid was assessed by immunoblotting and immunohistochemical methods in normal murine and human tissues, and in several types of human cancers and tumor cell lines. Bid expression in normal tissues varied widely, with prominent Bid immunostaining occurring in several types of short-lived cells (e.g., germinal center B cells, peripheral blood granulocytes, differentiated keratinocytes) and in apoptosis-sensitive cells (e.g., adult neurons). Analysis of Bid expression by immunostaining of 100 colon, 95 ovarian, and 254 prostate cancers, as well as 59 brain tumors and 50 lymphomas, revealed evidence of altered Bid regulation in some types of cancers. Correlations with clinical outcome data revealed association of higher levels of Bid with longer recurrence-free survival in men with locally advanced (T3 stage) prostate cancer (P=0.04). Immunoblot analysis of Bid protein levels in the NCI's panel of 60 human tumor cell lines revealed a correlation between higher levels of Bid and sensitivity to ribonucleotide reductase (RR)-inhibiting drugs (P<0.0005). Overexpression of Bid in a model tumor cell line by gene transfection resulted in increased sensitivity to apoptosis induction by a RR inhibitor. Taken together, these observations suggest a potential role for Bid in tumor responses to specific chemotherapeutic drugs, and lay a foundation for future investigations of this member of the Bcl-2 family in healthy and diseased tissues.

Role of the pro-survival molecule Bfl-1 in melanoma

“…Noxa has been shown to be upregulated in melanoma in response to proteasome inhibition resulting in cells becoming re-sensitized to apoptosis 301 , although again there is no evidence that loss of Noxa causes carcinogenesis. Interestingly, Bid appears to play an important role in cisplatin induced apoptosis in melanoma 302 , however in general it appears that Bid expression does not correlate with sensitivity to chemotherapy in many cancers 303 .…”

CD4 T Cell-Induced, Bid-Dependent Apoptosis of Cutaneous Dendritic Cells Regulates T Cell Expansion and Immune Responses

“…Interestingly, while Bid protein expression is restricted to neurons and to terminally differentiated cells fated to possesses short life spans (44), no increase in the rate of cancer development (including skin) has been documented, with the exception of a profound increase (53% in Bid KO vs 3% in WT) in the incidence of chronic myelomonocytic leukemia (48). This phenotype suggests that in young mice Bid-independent compensatory mechanisms exist to regulate tissue and cellular homeostasis, but with age, myeloid lineage cells have greater dependence on the type II apoptosis pathway for regulating their life span.…”

“…A limited immunohistochemical survey was done using anti-Bid sera (44). The strongest staining was detected in neuronal cells, stratified squamous epithelium, and in short-lived leukocytes (germinal center cells, granulocytes, macrophages), whereas monocytes, immature bone marrow cells, and cortical thymocytes were reported as negative.…”

Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities

“…Increases in Bax are found specifically in neurons that undergo cell death in ischemia-sensitive regions of the brain such as the CA1 sector of the hippocampus, in rat, hamster, and dog models of global cerebral ischemia. [26][27][28] Bax protein and mRNA levels also rapidly increase in neurons within the penumbra region of focal infarcts, in rodent models of middle cerebral artery occlusion. 29 Moreover, evidence suggesting a cause-and-effect relation between increases in Bax expression and ischemia-associated neuronal cell death has come from experiments using baxÀ/À mice generated by Korsmeyer et al 30 Elevations in Bax protein and mRNA levels were described in neurons in vivo after excitotoxic lesion with the N-methyl-D-aspartate receptor agonist, quinolinic acid, 31 as well as after systemic administration of kainic acid.…”