Evolution of a Gene

Markert, Clement L.; Shaklee, James B.; Whitt, Gregory S.

doi:10.1126/science.1138367

Cited by 526 publications

(162 citation statements)

References 192 publications

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“…While our data does not support that LDHB transcription is downstream of KRAS signaling, we hypothesize that a pathway functioning in parallel with KRAS activity might drive LDHB expression. In normal tissues, LDHB is expressed in liver, red blood cells, kidney, and heart, raising concern that its inhibition may have deleterious consequences (45,46). Intriguingly, however, patients with complete loss of LDHB expression due to a hereditary recessive trait have no significant phenotypic impairment (47,48).…”

Section: Discussionmentioning

confidence: 99%

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Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

McCleland¹,

Adler²,

Deming³

et al. 2013

Clinical Cancer Research

110

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Purpose: This study is aimed to identify genes within the KRAS genomic amplicon that are both coupregulated and essential for cell proliferation when KRAS is amplified in lung cancer.Experimental Design: We used an integrated genomic approach to identify genes that are coamplified with KRAS in lung adenocarcinomas and subsequently preformed an RNA interference (RNAi) screen to uncover functionally relevant genes. The role of lactate dehydrogenase B (LDHB) was subsequently investigated both in vitro and in vivo by siRNA and short hairpin RNA (shRNA)-mediated knockdown in a panel of lung adenocarcinoma cells lines. LDHB expression was also investigated in patient tumors using microarray and immunohistochemistry analyses.Results: RNAi-mediated depletion of LDHB abrogated cell proliferation both in vitro and in xenografted tumors in vivo. We find that LDHB expression correlates to both KRAS genomic copy number gain and KRAS mutation in lung cancer cell lines and adenocarcinomas. This correlation between LDHB expression and KRAS status is specific for lung cancers and not other tumor types that harbor KRAS mutations. Consistent with a role for LDHB in glycolysis and tumor metabolism, KRAS-mutant lung tumors exhibit elevated expression of a glycolysis gene signature and are more dependent on glycolysis for proliferation compared with KRAS wild-type lung tumors. Finally, high LDHB expression was a significant predictor of shorter survival in patients with lung adenocarcinomas.Conclusion: This study identifies LDHB as a regulator of cell proliferation in a subset of lung adenocarcinoma and may provide a novel therapeutic approach for treating lung cancer.

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Section: Discussionmentioning

confidence: 99%

“…Because the LDH enzymes function as both homoand heterotetramers (46), it is possible that reducing LDHB somehow affects LDHA activity and the forward reaction. However, an alternative explanation is that LDHB has an exclusive function from LDHA.…”

Section: Discussionmentioning

confidence: 99%

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

McCleland¹,

Adler²,

Deming³

et al. 2013

Clinical Cancer Research

110

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“…LDH, a tetrameric enzyme, is widely distributed among vertebrates, plants, and bacteria. In vertebrates there are three different subunits of LDH isozymes: LDH-A, LDH-B, and LDH-C (2). The LDH-A4 isozyme is best suited for pyruvate reduction in anaerobic tissues (muscle), whereas the LDH-B4 isozyme is superior for lactate oxidation in aerobic tissues (heart).…”

mentioning

confidence: 99%

Evolutionary relationships of lactate dehydrogenases (LDHs) from mammals, birds, an amphibian, fish, barley, and bacteria: LDH cDNA sequences from Xenopus, pig, and rat.

Tsuji

Qureshi

Hou

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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The nucleotide sequences of the cDNAs encoding LDH (EC 1.1.1.27) subunits LDH-A (muscle), LDH-B (liver), and LDH-C (oocyte) from Xenopus laevis, LDH-A (muscle) and LDH-B (heart) from pig, and LDH-B (heart) and LDH-C (testis) from rat were determined. These seven newly deduced amino acid sequences and 22 other published LDH sequences, and three unpublished fish LDH-A sequences kindly provided by G. N. Somero and D. A. Powers, were used to construct the most parsimonious phylogenetic tree of these 32 LDH subunits from mammals, birds, an amphibian, fish, barley, and bacteria. There have been at least six LDH gene duplications among the vertebrates. The Xenopus LDH-A, LDH-B, and LDH-C subunits are most closely related to each other and then are more closely related to vertebrate LDH-B than LDH-A. Three fish LDH-As, as well as a single LDH of lamprey, also seem to be more related to vertebrate LDH-B than to land vertebrate LDH-A. The mammalian LDH-C (testis) subunit appears to have diverged very early, prior to the divergence of vertebrate LDH-A and LDH-B subunits, as reported previously.

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“…LDH-A encodes LDH-A, also known as the M (muscle) subunit, and LDH-B encodes LDH-B, also known as the H (heart) subunit (11). (There is a third LDH-C gene, expressed restrictively in mature testis and sperm [9].) LDH-A and LDH-B combine to form 5 enzymatically active tetramers: A4, A1B3, A2B2, A3B1, and B4.…”

Section: Discussionmentioning

confidence: 99%

Physical therapy–induced rhabdomyolysis and acute kidney injury associated with reduced activity of muscle lactate dehydrogenase A

Lee¹,

Zand²,

Manek³

et al. 2011

Arthritis Care & Research

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Evolution of a Gene

Cited by 526 publications

References 192 publications

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

Evolutionary relationships of lactate dehydrogenases (LDHs) from mammals, birds, an amphibian, fish, barley, and bacteria: LDH cDNA sequences from Xenopus, pig, and rat.

Physical therapy–induced rhabdomyolysis and acute kidney injury associated with reduced activity of muscle lactate dehydrogenase A

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